3-Substituted-4-pyrimidone derivatives

ABSTRACT

a pyrimidone derivative represented by formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof having inhibitory activity against tau protein kinase 1: wherein R 1  represents a C 1 -C 12  alkyl group which may be substituted; R represents, for example, a group represented by the following formula (II): wherein R 2  and R 3  independently represent a hydrogen atom or a C 1 -C 8  alkyl group; R 4  represents a benzene ring which may be substituted, a naphthalene ring which may be substituted, an indan ring which may be substituted, a tetrahydronaphthalene ring which may be substituted, or an optionally substituted heterocyclic ring having 1 to 4 heteno atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, and having 5 to 10 ring-constituting atoms in total.

TECHNICAL FIELD

The present invention relates to compounds that are useful as an active ingredient of a medicament for preventive and/or therapeutic treatment of diseases mainly caused by abnormal activity of tau protein kinase 1, such as neurodegenerative diseases (e.g. Alzheimer disease).

BACKGROUND ART

Alzheimer disease is progressive senile dementia, in which marked cerebral cortical atrophy is observed due to degeneration of nerve cells and decrease of nerve cell number. Pathologically, numerous senile plaques and neurofibrillary tangles are observed in brain. The number of patients has been increased with the increment of aged population, and the disease arises a serious social problem. Although various theories have been proposed, a cause of the disease has not yet been elucidated. Early resolution of the cause has been desired.

It has been known that the degree of appearance of two characteristic pathological changes of Alzheimer disease well correlates to the degree of intellectual dysfunction. Therefore, researches have been conducted from early 1980's to reveal the cause of the disease through molecular level investigations of components of the two pathological changes. Senile plaques accumulate extracellularly, and β amyloid protein has been elucidated as their main component (abbreviated as “A β” hereinafter in the specification: Biochem. Biophys. Res. Commun., 120, 855 (1984); EMBO J., 4, 2757 (1985); Proc. Natl. Acad. Sci. USA, 82, 4245 (1985)). In the other pathological change, i.e., the neurofibrillary tangles, a double-helical filamentous substance called paired helical filament (abbreviated as ‘PHF’ hereinafter in the specification) accumulate intracellularly, and tau protein, which is a kind of microtubule-associated protein specific for brain, has been revealed as its main component (Proc. Natl. Acad. Sci. USA, 85, 4506 (1988); Neuron, 1, 827 (1988)).

Furthermore, on the basis of genetic investigations, presenilins 1 and 2 were found as causative genes of familial Alzheimer disease (Nature, 375, 754 (1995); Science, 269, 973 (1995); Nature. 376, 775 (1995)), and it has been revealed that presence of mutants of presenilins 1 and 2 promotes the secretion of A β (Neuron, 17, 1005 (1996); Proc. Natl. Acad. Sci. USA, 94, 2025 (1997)). From these results, it is considered that, in Alzheimer disease, A β abnormally accumulates and agglomerates due to a certain reason, which engages with the formation of PHF to cause death of nerve cells. It is also expected that extracellular outflow of glutamic acid and activation of glutamate receptor responding to the outflow may possibly be important factors in an early process of the nerve cell death caused by ischemic cerebrovascular accidents (Sai-shin Igaku [Latest Medicine], 49, 1506 (1994)).

It has been reported that kainic acid treatment that stimulates the AMPA receptor, one of glutamate receptor, increases mRNA of the amyloid precursor protein (abbreviated as “APP” hereinafter in the specification) as a precursor of A β (Society for Neuroscience Abstracts, 17, 1445 (1991)), and also promotes metabolism of APP (The Journal of Neuroscience, 10, 2400 (1990)). Therefore, it has been strongly suggested that the accumulation of A β is involved in cellular death due to ischemic cerebrovascular disorders. Other diseases in which abnormal accumulation and agglomeration of A β are observed include, for example, Down syndrome, cerebral bleeding due to solitary cerebral amyloid angiopathy, Lewy body disease (Shin-kei Shinpo [Nerve Advance], 34, 343 (1990); Tanpaku-shitu Kaku-san Koso [Protein, Nucleic Acid, Enzyme], 41, 1476 (1996)) and the like. Furthermore, as diseases showing neurofibrillary tangles due to the PHF accumulation, examples include progressive supranuclear palsy, subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis, Guam parkinsonism-dementia complex, Lewy body disease and the like (Tanpakushitu Kakusan Koso [Protein, Nucleic Acid, Enzyme], 36, 2 (1991); Igaku no Ayumi [Progress of Medicine], 158, 511 (1991); Tanpakushitu Kakusan Koso [Protein, Nucleic Acid, Enzyme], 41, 1476 (1996)).

The tau protein is generally composed of a group of related proteins that forms several bands at molecular weights of 48-65 kDa in SDS-polyacrylamide gel electrophoresis, and it promotes the formation of microtubules. It has been verified that tau protein incorporated in the PHF in the brain suffering from Alzheimer disease is abnormally phosphorylated compared with usual tau protein (J. Biochem., 99, 1807 (1986); Proc. Natl. Acad. Sci. USA, 83, 4913 (1986)). An enzyme catalyzing the abnormal phosphorylation has been isolated. The protein was named as tau protein kinase 1 (abbreviated as “TPK1” hereinafter in the specification), and its physicochemical properties have been elucidated (Seikagaku [Biochemistry], 64, 308 (1992); J. Biol. Chem., 267, 10897 (1992)). Moreover, cDNA of rat TPK1 was cloned from a rat cerebral cortex cDNA library based on a partial amino acid sequence of TPK1, and its nucleotide sequence was determined and an amino acid sequence was deduced (Japanese Patent Un-examined Publication [Kokai] No. 6-239893/1994). As a result, it has been revealed that the primary structure of the rat TPK1 corresponds to that of the enzyme known as rat GSK-3β (glycogen synthase kinase 3β, FEBS Lett., 325, 167 (1993)).

It has been reported that A β the main component of senile plaques, is neurotoxic (Science, 250, 279 (1990)). However, various theories have been proposed as for the reason why A β causes the cell death, and any authentic theory has not yet been established. Takashima et al. observed that the cell death was caused by A β treatment of fetal rat hippocampus primary culture system, and then found that the TPK1 activity was increased by A β treatment and the cell death by A β was inhibited by antisense of TPK1 (Proc. Natl. Acad. Sci. USA, 90, 7789 (1993); Japanese Patent Un-examined Publication [Kokai] No. 6-329551/1994).

In view of the foregoing, compounds which inhibit the TPK1 activity may possibly suppress the neurotoxicity of A β and the formation of PHF and inhibit the nerve cell death in the Alzheimer disease, thereby cease or defer the progress of the disease. The compounds may also be possibly used as a medicament for therapeutic treatment of ischemic cerebrovascular disorder, Down syndrome, cerebral amyloid angiopathy, cerebral bleeding due to Lewy body disease and the like by suppressing the cytotoxicity of A β. Furthermore, the compounds may possibly be used as a medicament for therapeutic treatment of neurodegenerative diseases such as progressive supranuclear palsy, subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis, Guam parkinsonism-dementia complex, Lewy body disease, Pick's disease, corticobasal degeneration, frontotemporal dementia, vascular dementia, traumatic injuries, brain and spinal cord trauma, peripheral neuropathies, retinopathies and glaucoma, as well as other diseases such as non-insulin dependent diabetes, obesity, manic depressive illness, schizophrenia, alopecia, breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia, and several virus-induced tumors.

As structurally similar compounds to the compounds of the present invention represented by formula (I) described later, compounds represented by the following formula (A) are known:

wherein R represents 2,6-dichlorobenzyl group, 2-(2-chlorophenyl)ethylamino group, 3-phenylpropylamino group, or 1-methyl-3-phenylpropylamino group (WO98/24782). The compounds represented by formula (A) are characterized to have 4-fluorophenyl group at the 5-position of the pyrimidine ring and a hydroxy group at the 4-position, and not falling within the scope of the present invention. Moreover, main pharmacological activity of the compounds represented by formula (A) is anti-inflammatory effect, whereas the compounds of the present invention represented by formula (I) are useful as a TPK1 inhibitor or a medicament for therapeutic treatment of neutodegenerative diseases, and therefore, their pharmacological activities are totally different to each other.

OBJECT TO BE ACHIEVED BY THE INVENTION

An object of the present invention is to provide compounds useful as an active ingredient of a medicament for preventive and/or therapeutic treatment of diseases such as Alzheimer disease. More specifically, the object is to provide novel compounds useful as an active ingredient of a medicament that enables radical prevention and/or treatment of the neurodegenerative diseases such as Alzheimer disease by inhibiting the TPK1 activity to suppress the neurotoxicity of A β and the formation of the PHF and by inhibiting the death of nerve cells.

MEANS TO ACHIEVE THE OBJECT

In order to achieve the foregoing object, the inventors of the present invention conducted screenings of various compounds having inhibitory activity against the phosphorylation of TPK1. As a result, they found that compounds represented by the following formula (I) had the desired activity and were useful as an active ingredient of a medicament for preventive and/or therapeutic treatment of the aforementioned diseases. The present invention was achieved on the basis of these findings.

The present invention thus provide a pyrimidone derivative represented by formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof:

wherein R¹ represents a C₁-C₁₂ alkyl group which may be substituted;

-   R represents any one of groups represented by the following     formulas (II) to (V):     wherein R² and R³ independently represent a hydrogen atom or a C₁-C₈     alkyl group; -   R⁴ represents a benzene ring which may be substituted, a naphthalene     ring which may be substituted, an indan ring which may be     substituted, a tetrahydronaphthalene ring which may be substituted,     or an optionally substituted heterocyclic ring having 1 to 4 hetero     atoms selected from the group consisting of oxygen atom, sulfur atom     and nitrogen atom, and having 5 to 10 ring-constituting atoms in     total; -   R⁵ represents a C₁-C₈ alkyl group which may be substituted, a C₃-C₈     cycloalkyl group which may be substituted, a benzene ring which may     be substituted, a naphthalene ring which may be substituted, an     indan ring which may be substituted, a tetrahydronaphthalene ring     which may be substituted, or an optionally substituted heterocyclic     ring having 1 to 4 hetero atoms selected from the group consisting     of oxygen atom, sulfur atom, and nitrogen atom, and having 5 to 10     ring-constituting atoms in total; -   R⁶ represents a hydrogen atom, a C₁-C₈ alkyl group which may be     substituted, a benzene ring which may be substituted; -   or R⁵ and R⁶ may bind to each other to form together with the carbon     to which R⁵ and R⁶ are attached an optionally substituted spiro     carbocyclic ring having 3 to 11 ring-constituting atoms in total; -   R⁷ and R⁸ independently represent a hydrogen atom or a C₁-C₈ alkyl     group, or R⁷ and -   R⁸ may combine to each other to form a C₂-C₆ alkylene group; -   R⁹ and R¹⁰ represent a C₁-C₈ alkyl group which may be substituted, a     C₃-C₈ cycloalkyl group which may be substituted, a benzene ring     which may be substituted, a naphthalene ring which may be     substituted, an optionally substituted heterocyclic ring having 1 to     4 hetero atoms selected from the group consisting of oxygen atom,     sulfur atom, and nitrogen atom, and having 5 to 10 ring-constituting     atoms in total, or R⁹ and R¹⁰ represent —N(R¹¹)(R¹²) wherein R¹¹     represents a hydrogen atom, a C₁-C₈ alkyl group; and R¹² represents     a C₁-C₈ alkyl group, a benzene ring which may be substituted, a     naphthalene ring which may be substituted, or an optionally     substituted heterocyclic ring having 1 to 4 hetero atoms selected     from the group consisting of oxygen atom, sulfur atom, and nitrogen     atom, and having 5 to 10 ring-constituting atoms in total; -   and X represents CH₂, O or NR¹³ wherein R¹³ represents a hydrogen     atom or a C₁-C₈ alkyl group.

According to preferred embodiments of the present invention, provided are:

-   -   the aforementioned pyrimidone derivative or the salt thereof, or         the solvate thereof or the hydrate thereof, wherein R¹ is methyl         group;     -   the aforementioned pyrimidone derivative or the salt thereof, or         the solvate thereof or the hydrate thereof, wherein R is the         group represented by formula (II);     -   the aforementioned pyrimidone derivative or the salt thereof, or         the solvate thereof or the hydrate thereof, wherein each of R²         and R³ is hydrogen atom;     -   the aforementioned pyrimidone derivative or the salt thereof, or         the solvate thereof or the hydrate thereof, wherein R is the         group represented by formula (III);     -   the aforementioned pyrimidone derivative or the salts thereof,         or the solvate thereof or the hydrate thereof, wherein R⁶ is         hydrogen atom;     -   the aforementioned pyrimidone derivative or the salts thereof,         or the solvate thereof or the hydrate thereof, wherein each of         R⁷ and R⁸ is hydrogen atom;     -   the aforementioned pyrimidone derivative or the salts thereof,         or the solvate thereof or the hydrate thereof, wherein each of         R⁷ and R⁸ is methyl group;     -   the aforementioned pyrimidone derivative or the salt thereof, or         the solvate thereof or the hydrate thereof, wherein R is the         group represented by formula (IV);     -   the aforementioned pyrimidone derivative or the salts thereof,         or the solvate thereof or the hydrate thereof, wherein R⁹ is a         benzene ring which may be substituted;     -   the aforementioned pyrimidone derivative or the salts thereof,         or the solvate thereof or the hydrate thereof, wherein X is CH₂;     -   the aforementioned pyrimidone derivative or the salts thereof,         or the solvate thereof or the hydrate thereof, wherein X is O;     -   the aforementioned pyrimidone derivative or the salt thereof, or         the solvate thereof or the hydrate thereof, wherein R is the         group represented by formula (V);     -   the aforementioned pyrimidone derivative or the salts thereof,         or the solvate thereof or the hydrate thereof, wherein R¹⁰ is a         benzene ring which may be substituted; and     -   the aforementioned pyrimidone derivative or the salts thereof,         or the solvate thereof or the hydrate thereof, wherein R¹⁰ is a         heterocyclic ring having 1 to 4 hetero atoms selected from the         group consisting of oxygen atom, sulfur atom, and nitrogen atom,         and having total ring-constituting atoms of 5 to 10 which may be         substituted.

From another aspect, the present invention provides a medicament comprising as an active ingredient a substance selected from the group consisting of the pyrimidone derivative represented by the aforementioned formula (I) and a salt thereof, and a solvate thereof and a hydrate thereof, and a tau protein kinase 1 inhibitor selected from the group consisting of the pyrimidone derivative represented by the aforementioned formula (I) and a salt thereof, and a solvate thereof and a hydrate thereof.

According to preferred embodiments of the aforementioned medicament, provided are the aforementioned medicament which is used for preventive and/or therapeutic treatment of a disease caused by tau protein kinase 1 hyperactivity;

-   -   the aforementioned medicament which is used for preventive         and/or therapeutic treatment of a neurodegenerative disease;     -   the aforementioned medicament, wherein the disease is selected         from the group consisting of Alzheimer disease, ischemic         cerebrovascular accidents, Down syndrome, cerebral bleeding due         to cerebral amyloid angiopathy, progressive supranuclear palsy,         subacute sclerosing panencephalitic parkinsonism,         postencephalitic parkinsonism, pugilistic encephalitis, Guam         parkinsonism-dementia complex, Lewy body disease, Pick's         disease, corticobasal degeneration, frontotemporal dementia,         vascular dementia, traumatic injuries, brain and spinal cord         trauma, peripheral neuropathies, retinopathies and glaucoma; and     -   the aforementioned medicament, wherein the disease is selected         from the group consisting of non-insulin dependent diabetes,         obesity, manic depressive illness, schizophrenia, alopecia,         breast cancer, non-small cell lung carcinoma, thyroid cancer, T         or B-cell leukemia, and a virus-induced tumor.

According to further aspects of the present invention, there are provided a method for preventive and/or therapeutic treatment of a disease caused by tau protein kinase 1 hyperactivity, which comprises the step of administering to a patient a preventively and/or therapeutically effective amount of a substance selected from the group consisting of the 3-substituted-4-pyrimidone derivative of formula (I) and the physiologically acceptable salt thereof, and the solvate thereof and the hydrate thereof; and a use of a substance selected from the group consisting of the 3-substituted-4-pyrimidone derivative of formula (I) and the physiologically acceptable salt thereof, and the solvate thereof and the hydrate thereof for the manufacture of the aforementioned medicament.

From further aspect of the present invention, provided are a pyrimidone derivative represented by formula (VI) or a salt thereof, or a solvate thereof or a hydrate thereof:

wherein R¹ represents a C₁-C₁₂ alkyl group which may be substituted, and a pyrimidone derivative represented by formula (VII) or a salt thereof, or a solvate thereof or a hydrate thereof:

-   -   wherein R¹ represents a C₁-C₁₂ alkyl group which may be         substituted.

BEST MODE FOR CARRYING OUT THE INVENTION

The alkyl group used herein may be either linear or branched. The C₁-C₁₂ alkyl group represented by R¹ may be, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, 1,1-dimethylpropyl group, n-hexyl group, isohexyl group, or a linear or branched heptyl group, octyl group, nonyl group, decyl group, undecyl group or dodecyl group. In the specification, when a functional group is defined as “which may be substituted” or “optionally substituted”, the number of substituents as well as their types and substituting positions are not particularly limited, and when two or more substituents are present, they may be the same or different.

When the C₁-C₁₂ alkyl group represented by R¹ has one or more substituents, the alkyl group may have one or more substituents selected from the group consisting of a C₁-C₅ alkoxyl group such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, tert-butoxy group; amino group, C₁-C₃ alkylamino group or C₂-C₆ dialkylamino group: a C₆-C₁₀ aryl group such as phenyl group, 1-naphthyl group, and 2-naphthyl group;

The C₁-C₈ alkyl group represented by R² or R³ may be, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, 1,1-dimethylpropyl group, n-hexyl group, isohexyl group, or a linear or branched heptyl group or octyl group.

When the benzene ring, the naphthalene ring, the indan ring, the tetrahydronaphthalene ring, or the heterocyclic ring represented by R⁴ or R⁵ has one or more substituents, the rings may have one or more substituents selected from the groups consisting of a C₁-C₅ alkyl group such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, 1,1-dimethylpropyl group; C₃-C₆ cycloalkyl group such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group; a C₃-C₆ cycloalkyloxy group such as cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group; a C₁-C₅ alkoxyl group such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, tert-butoxy group, pentyloxy group, and isopentyloxy group; a C₄-C₇ cycloalkylalkoxy group such as cyclopropylmethoxy group, cyclopentylmethoxy group; a C₁-C₅ alkylthio group such as methylthio group, ethylthio group, propylthio group, butylthio group, and pentylthio group; a C₁-C₅ alkylsulfonyl group such as methanesulfonyl group, ethanesulfonyl group, propanesulfonyl group, butanesulfonyl group, and pentanesulfonyl group; a halogen atom such as fluorine atom, chlorine atom, bromine atom, and iodine atom; a C₁-C₅ halogenated alkyl group such as trifluoromethyl group; a C₁-C₅ halogenated alkoxy group such as trifluoromethoxy group, 2,2,2-trifluoroethoxy group; hydroxyl group; cyano group; nitro group; formyl group; a C₂-C₆ alkylcarbonyl group such as acetyl group, propionyl group, butyryl group, and valeryl group; benzene ring which may be substituted, naphthalene ring which may be substituted, an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, and having 5 to 10 ring-constituting atoms, phenoxy group which may be substituted or phenylamino group which may be substituted; amino group; a C₁-C₅ monoalkylamino group such as methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, tert-butylamino group, pentylamino group, and isopentylamino group; a C₂-C₁₀ dialkylamino group such as dimethylamino group, ethylmethylamino group, diethylamino group, methylpropylamino group, and diisopropylamino group; a C₂-C₁₀ monoalkylaminomethyl group such as methylaminomethyl group, ethylaminomethyl group, propylaminomethyl group, isopropylaminomethyl group, butylaminomethyl group, isobutylaminomethyl group, tert-butylaminomethyl group, pentylaminomethyl group, isopentylaminomethyl group; a C₃-C₁₁ dialkylaminomethyl group such as dimethylaminomethyl group, diethylaminomethyl group, ethylmethylaminomethyl group, methylpropylaminomethyl group; pyrrolidinylmethyl group; piperidinylmethyl group; morpholinomethyl group; piperazinylmethyl group; pyrrolylmethyl group; imidazolylmethyl group; pyrazolylmethyl group; and triazolylmethyl group.

When the benzene ring, the naphthalene ring, the indan ring, the tetrahydronaphthalene ring or the heterocyclic ring has one or more substituents, the substituent may further have one or more substituents selected from the group consisting of a C₁-C₆ alkyl group such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, 1,1-dimethylpropyl group; C₃-C₆ cycloalkyl group such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group; a C₃-C₆ cycloalkyloxy group such as cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group; a C₁-C₅ alkoxy group such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, tert-butoxy group, pentyloxy group, and isopentyloxy group; a C₄-C₇ cycloalkylalkoxy group such as cyclopropylmethoxy group, cyclopentylmethoxy group; a C₁-C₅ alkylthio group such as methylthio group, ethylthio group, propylthio group, butylthio group, and pentylthio group; a C₁-C₅ alkylsulfonyl group such as methanesulfonyl group, ethanesulfonyl group, propanesulfonyl group, butanesulfonyl group, and pentanesulfonyl group; a halogen atom such as fluorine atom, chlorine atom, bromine atom, and iodine atom; a C₁-C₅ halogenated alkyl group such as trifluoromethyl group; a C₁-C₅ halogenated alkoxy group such as trifluoromethoxy group, 2,2,2-trifluoroethoxy group; hydroxyl group; cyano group; nitro group; formyl group; a C₂-C₆ alkylcarbonyl group such as acetyl group, propionyl group, butyryl group, and valeryl group; amino group; a C₁-C₅ monoalkylamino group such as methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, tert-butylamino group, pentylamino group, and isopentylamino group; a C₂-C₁₀ dialkylamino group such as dimethylamino group, ethylmethylamino group, diethylamino group, methylpropylamino group, and diisopropylamino group; a C₂-C₁₀ monoalkylaminomethyl group such as methylaminomethyl group, ethylaminomethyl group, propylaminomethyl group, isoproylaminomethyl group, butylaminomethyl group, isobutylaminomethyl group, tert-butylaminomethyl group, pentylaminomethyl group, isopentylaminomethyl group; a C₃-C₁₁ dialkylaminomethyl group such as dimethylaminomethyl group, diethylaminomethyl group, ethylmethylaminomethyl group, methylpropylaminomethyl group and the like.

The heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom, and nitrogen atom, and having 5 to 10 ring-constituting atoms represented by R⁴ or R⁵ may be, for example, furan ring, dihydrofuran ring, tetrahydrofuran ring, pyran ring, dihydropyran ring, tetrahydropyran ring, benzofuran ring, dihydrobenzofuran, isobenzofuran ring, benzodioxole ring, chromene ring, chroman ring, isochroman ring, thiophene ring, benzothiophene ring, pyrrole ring, pyrroline ring, pyrrolidine ring, imidazole ring, imidazoline ring, imidazolidine ring, pyrazole ring, pyrazoline ring, pyrazolidine ring, triazole ring, tetrazole ring, pyridine ring, pyridine oxide ring, piperidine ring, pyrazine ring, piperazine ring, pyrimidine ring, pyridazine ring, indole ring, indoline ring, isoindole ring, isoindoline ring, indazole ring, benzimidazole ring, benzotriazole ring, tetrahydroisoquinoline ring, benzothiazolinone ring, benzoxazolinone ring, purine ring, quinolizine ring, quinoline ring, phthalazine ring, naphthyridine ring, quinoxaline ring, quinazoline ring, cinnoline ring, pteridine ring, oxazole ring, oxazolidine ring, isoxazole ring, isoxazolidine ring, oxadiazole ring, thiazole ring, benzothiazole ring, thiazylidine ring, isothiazole ring, isothiazolidine ring, benzodioxole ring, dioxane ring, benzodioxane ring, dithian ring, morpholine ring, thiomorpholine ring, and phthalimide ring.

The C₁-C₈ alkyl group represented by R⁵, R⁶, R⁷ or R⁸ may be, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, 1,1-dimethylpropyl group, n-hexyl group, isohexyl group, or a linear or branched heptyl group or octyl group.

The C₃-C₈ cycloalkyl group represented by R⁵ may be, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group or cyclooctyl group.

When the C₁-C₈ alkyl group or C₃-C₈ cycloalkyl group represented by R⁵ or the C₁-C₈ alkyl group represented by R⁶ has one or more substituents, the group may have one or more substituents selected from the groups consisting of a halogen atom, a C₁-C₆ alkoxyl group, a C₃-C₈ cycloalkyl group, a benzene ring which may be substituted, a naphthalene ring which may be substituted, phenoxy group which may be substituted or phenylamino group which may be substituted; amino group, a C₁-C₆ alkylamino group, a C₂-C₁₂ dialkylamino group, 1-pyrrolidinyl group, 1-pyperidinyl group, 1-morpholinyl group, 1-(tetrahydro-1,2,3,4-quinolinyl) group, or 1-(tetrahydro-1,2,3,4-isoquinolinyl) group.

When the benzene ring represented by R⁵ has one or more substituents, the ring may have one or more substituents selected from the group consisting of a C₁-C₀ alkyl group such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, 1,1-dimethylpropyl group; a C₃-C₆ cycloalkyl group such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group; a C₃-C₆ cycloalkyloxy group such as cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group; a C₁-C₅ alkoxyl group such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, tert-butoxy group, pentyloxy group, and isopentyloxy group; a C₄-C₇ cycloalkylalkoxyl group such as cyclopropylmethoxy group, cyclopentylmethoxy group; a C₁-C₅ alkylthio group such as methylthio group, ethylthio group, propylthio group, butylthio group, and pentylthio group; a C₁-C₅ alkylsulfonyl group such as methanesulfonyl group, ethanesulfonyl group, propanesulfonyl group, butanesulfonyl group, and pentanesulfonyl group; a halogen atom such as fluorine atom, chlorine atom, bromine atom, and iodine atom; a C₁-C₅ halogenated alkyl group such as trifluoromethyl group; a C₁-C₅ halogenated alkoxyl group such as trifluoromethoxy group, 2,2,2-trifluoroethoxy group; hydroxyl group; cyano group; nitro group; formyl group; a C₂-C₆ alkylcarbonyl group such as acetyl group, propionyl group, butyryl group, and valeryl group; a benzene ring which may be substituted, a naphthalene ring which may be substituted, an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, and having 5 to 10 ring-constituting atoms, phenoxy group which may be substituted or phenylamino group which may be substituted; amino group; a C₁-C₅ monoalkylamino group such as methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, tert-butylamino group, pentylamino group, and isopentylamino group; a C₂-C₁₀ dialkylamino group such as dimethylamino group, etbylmethylamino group, diethylamino group, methylpropylamino group, and diisopropylamino group; a C₂-C₁₀ monoalkylaminomethyl group such as methylaminomethyl group, ethylaminomethyl group, propylaminomethyl group, isopropylaminomethyl group, butylaminomethyl group, isobutylaminomethyl group, tert-butylaminomethyl group, pentylaminomethyl group, isopentylaminomethyl group; a C₃-C₁₁ dialkylaminomethyl group such as dimethylaminomethyl group, diethylaminomethyl group, ethylmethylaminomethyl group, methylpropylaminomethyl group; pyrrolidinylmethyl group; pipelidinylmethyl group; morpholinomethyl group; piperazinylmethyl group; pyrrolylmethyl group; imidazolylmethyl group; pyrazolylmethyl group; triazolylmethyl group.

When the benzene ring represented by R⁶ has one or more substituents, the substituent may further have one or more substituents selected from the groups consisting of a C₁-C₅ alkyl group such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, 1,1-dimethylpropyl group; C₈-C₆ cycloalkyl group such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group; a C₃-C₆ cycloalkyloxy group such as cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group; a C₁-C₅ alkoxyl group such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, tert-butoxy group, pentyloxy group, and isopentyloxy group; a C₄-C₇ cycloalkylalkoxyl group such as cyclopropylmethoxy group, cyclopentylmethoxy group; a C₁-C₅ alkylthio group such as methylthio group, ethylthio group, propylthio group, butylthio group, and pentylthio group; a C₁-C₅ alkylsulfonyl group such as methanesulfonyl group, ethanesulfonyl group, propanesulfonyl group, butanesulfonyl group, and pentanesulfonyl group; a halogen atom such as fluorine atom, chlorine atom, bromine atom, and iodine atom; a C₁-C₅ halogenated alkyl group such as trifluoromethyl group; a C₁-C₅ halogenated alkoxyl group such as trifluoromethoxy group, 2,2,2-trifluoroethoxy group; hydroxyl group; cyano group; nitro group; formyl group; a C₂-C₆ alkylcarbonyl group such as acetyl group, propionyl group, butyryl group, and valeryl group; amino group; a C₁-C₅ monoalkylamino group such as methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, tert-butylamino group, pentylamino group, and isopentylamino group; a C₂-C₁₀ dialkylamino group such as dimethylamino group, ethylmethylamino group, diethylamino group, methylpropylamino group, and diisopropylamino group; a C₂-C₁₀ monoalkylaminomethyl group such as methylaminomethyl group, ethylaminomethyl group, propylaminomethyl group, isopropylaminomethyl group, butylaminomethyl group, isobutylaminomethyl group, tert-butylaminomethyl group, pentylaminomethyl group, isopentylaminomethyl group; a C₃-C₁₁ dialkylaminomethyl group such as dimethylaminomethyl group, diethylaminomethyl group, ethylmethylaminomethyl group, methylpropylaminomethyl group.

When R⁵ and R⁶ combine to each other to form a spiro carbocyclic ring, together with the carbon atom to which R⁵ and R⁶ bind, the carbocyclic ring may be, for example, cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, cyclohexyl ring, cycloheptyl ring, tetrahydrobenzocycloheptene ring, tetrahydronaphthalene ring, indane ring, bicyclo[4,2,0]octa-1,3,5-triene ring.

The C₁-C₈ alkyl group represented by R⁹, R¹⁰, R¹¹, R¹² or R¹³ may be, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, 1,1-dimethylpropyl group, n-hexyl group, isohexyl group, or a linear or branched heptyl group or octyl group.

The C₃-C₈ cycloalkyl group represented by R⁹ or R¹⁰ may be, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group or cyclooctyl group.

When the C₁-C₈ alkyl group or C₃-C₈ cycloalkyl group represented by R⁹ or R¹⁰ has one or more substituents, the group may have one or more substituents selected from, for example, the groups consisting of a halogen atom, C₃-C₈ cycloalkyl group, a benzene ring which may be substituted, a naphthalene ring which may be substituted, an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, and having 5 to 10 ring-constituting atoms in total.

When the benzene ring, the naphthalene ring or the heterocyclic ring represented by R⁹ or R¹⁰ has one or more substituents, the ring may have one or more substituents selected form the group consisting of a C₁-C₅ alkyl group such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, 1,1-dimethylpropyl group; C₃-C₆ cycloalkyl group such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group; a C₃-C₆ cycloalkyloxy group such as cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group; a C₁-C₅ alkoxy group such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, tert-butoxy group, pentyloxy group, and isopentyloxy group; a C₄-C₇ cycloalkylalkoxyl group such as cyclopropylmethoxy group, cyclopentylmethoxy group; a C₁-C₅ alkylthio group such as methylthio group, ethylthio group, propylthio group, butylthio group, and pentylthio group; a C₁-C₅ alkylsulfonyl group such as methanesulfonyl group, ethanesulfonyl group, propanesulfonyl group, butanesulfonyl group, and pentanesulfonyl group; a halogen atom such as fluorine atom, chlorine atom, bromine atom, and iodine atom; a C₁-C₅ halogenated alkyl group such as trifluoromethyl group; a C₁-C₅ halogenated alkoxyl group such as trifluoromethoxy group, 2,2,2-trifluoroethoxy group; hydroxyl group; cyano group; nitro group; formyl group; a C₂-C₆ alkylcarbonyl group such as acetyl group, propionyl group, butyryl group, and valeryl group; a benzene ring which may be substituted, a naphthalene ring which may be substituted, an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, and having 5 to 10 ring-constituting atoms in total; a phenoxy group which may be substituted; a phenylamino group which may be substituted; an amino group; a C₁-C₅ monoalkylamino group such as methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, tert-butylamino group, pentylamino group, and isopentylamino group; a C₂-C₁₀ dialkylamino group such as dimethylamino group, ethylmethylamino group, diethylamino group, methylpropylamino group, and diisopropylamino group; a C₁-C₅ monoalkylaminomethyl group such as methylaminomethyl group, ethylaminomethyl group, propylaminomethyl group, isopropylaminomethyl group, butylaminomethyl group, isobutylaminomethyl group, tert-butylaminomethyl group, pentylaminomethyl group, isopentylaminomethyl group; a C₂-C₁₀ dialkylaminomethyl group such as dimethylaminomethyl group, diethylaminomethyl group, ethylmethylaminomethyl group, methylpropylaminomethyl group; pyrrolidinylmethyl group; piperidinylmethyl group; morpholinomethyl group; piperazinylmethyl group; pyrrolylmethyl group; imidazolylmethyl group; pyrazolylmethyl group; and triazolylmethyl group.

The heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom, and nitrogen atom, and having 5 to 10 ring-constituting atoms in total represented by R⁹ or R¹⁰ may be, for example, furan ring, dihydrofuran ring, tetrahydrofuran ring, pyran ring, dihydropyran ring, tetrahydropyran ring, benzofuran ring, dihydrobenzofuran, isobenzofuran ring, benzodioxol ring, chromene ring, chroman ring, isochroman ring, thiophene ring, benzothiophene ring, pyrrole ring, pyrroline ring, pyrrolidine ring, imidazole ring, imidazoline ring, imidazolidine ring, pyrazole ring, pyrazoline ring, pyrazolidine ring, triazole ring, tetrazole ring, pyridine ring, pyridine oxide ring, piperidine ring, pyrazine ring, piperazine ring, pyrimidine ring, pyridazine ring, indole ring, indoline ring, isoindole ring, isoindoline ring, indazole ring, benzimidazole ring, benzotriazole ring, tetrahydroisoquinoline ring, benzothiazolinone ring, benzoxazolinone ring, purine ring, quinolizine ring, quinoline ring, phthalazine ring, naphthyridine ring, quinoxaline ring, quinazoline ring, cinnoline ring, pteridine ring, oxazole ring, oxazolidine ring, isoxazole ring, isoxazolidine ring, oxadiazole ring, thiazole ring, benzothiazole ring, thiazylidine ring, isothiazole ring, isothiazolidine ring, benzodioxole ring, dioxane ring, benzodioxane ring, dithian ring, morpholine ring, thiomorpholine ring, or phthalimide ring.

When the benzene ring, the naphthalene ring, or the heterocyclic ring represented by R¹² has one or more substituents, the ring may be substituted by one or more substituents selected from the groups consisting of halogen atoms, a C₁-C₅ alkyl group, a C₃-C₆ cycloalkyl group, a C₃-C₆ cycloalkyloxy group, a C₁-C₅ alkoxy group, a C₄-C₇ cycloalkylalkoxy, a C₁-C₅ alkylthio group, a C₁-C₅ alkylsulfonyl group, a C₁-C₅ halogenated alkyl, and a benzene ring.

When the benzene ring, the naphthalene ring or the heterocyclic ring has one or more substituents, the substituent may further have one or more substituents selected from the group consisting of a C₁-C₆ alkyl group such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, 1,1-dimethylpropyl group; C₃-C₆ cycloalkyl group such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group; a C₃-C₆ cycloalkyloxy group such as cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group; a C₁-C₅ alkoxy group such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, tert-butoxy group, pentyloxy group, and isopentyloxy group; a C₄-C₇ cycloalkylalkoxy group such as cyclopropylmethoxy group, cyclopentylmethoxy group; a C₁-C₅ alkylthio group such as methylthio group, ethylthio group, propylthio group, butylthio group, and pentylthio group; a C₁-C₅ alkylsulfonyl group such as methanesulfonyl group, ethanesulfonyl group, propanesulfonyl group, butanesulfonyl group, and pentanesulfonyl group; a halogen atom such as fluorine atom, chlorine atom, bromine atom, and iodine atom; a C₁-C₅ halogenated alkyl group such as trifluoromethyl group; a C₁-C₅ halogenated alkoxy group such as trifluoromethoxy group, 2,2,2-trifluoroethoxy group; hydroxyl group; cyano group; nitro group; formyl group; a C₂-C₆ alkylcarbonyl group such as acetyl group, propionyl group, butyryl group, and valeryl group; amino group; a C₁-C₅ monoalkylamino group such as methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, tert-butylamino group, pentylamino group, and isopentylamino group; a C₂-C₁₀ dialkylamino group such as dimethylamino group, ethylmethylamino group, diethylamino group, methylpropylamino group, and diisopropylamino group; a C₂-C₁₀ monoalkylaminomethyl group such as methylaminomethyl group, ethylaminomethyl group, propylaminomethyl group, isopropylaminomethyl group, butylaminomethyl group, isobutylaminomethyl group, tert-butylaminomethyl group, pentylaminomethyl group, isopentylaminomethyl group; a C₃-C₁₁ dialkylaminomethyl group such as dimethylaminomethyl group, diethylaminomethyl group, ethylmethylaminomethyl group, methylpropylaminomethyl group and the like.

R¹ may preferably be a C₁-C₃ alkyl group, more preferably a methyl group.

R² may preferably be a hydrogen atom.

R³ may preferably be a hydrogen atom.

R⁴ may preferably be a benzene ring which may be substituted.

R⁵ may preferably be a benzene ring or a naphthalene ring which may be substituted.

R⁶ may preferably be a hydrogen atom.

R⁷ and R⁸ may preferably be a hydrogen atom or a C₁-C₃ alkyl group.

R⁹ or R¹⁰ may preferably be a benzene ring which may be substituted.

R¹⁰ may preferably be a heterocyclic ring having 1-4 hetero atoms selected oxygen atom, sulfur atom and nitrogen atom, and having total ring-constituting atoms of 5-10 which may be substituted. Particularly preferred R¹⁰ is a benzene ring which may be substituted, a 2,3-dihydroindole ring which may be substituted, or 3,4-dihydro-2H-quinoline ring which may be substituted.

Particularly preferred X is CH₂ or O.

The compounds represented by the aforementioned formula (I) may form a salt. Examples of the salt include, when an acidic group exists, salts of alkali metals and alkaline earth metals such as lithium, sodium, potassium, magnesium, and calcium; salts of ammonia and amines such as methylamine, dimethylamine, trimethylamine, dicyclohexylamine, tris(hydroxymethyl)aminomethane, N,N-bis(hydroxyethyl)piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, and L-glucamine; or salts with basic amino acids such as lysine, 6-hydroxylysine, and arginine. When a basic group exists, examples include salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; salts with organic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, propionic acid, tartaric acid, fumaric acid, maleic acid, malic acid, oxalic acid, succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid, lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinic acid, and salicylic acid; or salts with acidic amino acids such as aspartic acid, and glutamic acid.

In addition to the 3-substituted-4-pyrimidone derivatives represented by the aforementioned formula (I) and salts thereof, their solvates and hydrates also fall within the scope of the present invention. The 3-substituted-4-pyrimidone derivatives represented by the aforementioned formula (I) may have one or more asymmetric carbon atoms. As for the stereochemistry of such asymmetric carbon atoms, they may independently be in either (R) and (S) configuration, and the pyrimidone derivative may exist as stereoisomers such as optical isomers, or diastereoisomers. Any stereoisomers of pure form, any mixtures of stereoisomers, racemates and the like fall within the scope of the present invention.

Examples of preferred compounds of the present invention are shown in the table below. However, the scope of the present invention is not limited by the following compounds. Com- pound No. STRUCTURE A001

A002

A003

A004

A005

A006

A007

A008

A009

A010

A011

A012

A013

A014

A015

A016

A017

A018

A019

A020

A021

A022

A023

A024

A025

A026

A027

A028

A029

A030

A031

A032

A033

A034

A035

A036

A037

A038

A039

A040

A041

A042

A043

A044

A045

A046

A047

A048

A049

A050

A051

A052

A053

A054

A055

A056

A057

A058

A059

A060

A061

A062

A063

A064

A065

A066

A067

A068

A069

A070

A071

A072

A073

A074

A075

A076

A077

A078

A079

A080

A081

A082

A083

A084

A085

A086

A087

A088

A089

A090

A091

A092

A093

A094

A095

A096

A097

A098

A099

A100

A101

A102

A103

A104

A105

A106

A107

A108

A109

A110

A111

A112

A113

A114

A115

A116

A117

A118

B001

B002

B003

B004

B005

B006

B007

B008

B009

B010

B011

B012

B013

B014

B015

B016

B017

B018

B019

B020

B021

B022

B023

B024

B025

B026

B027

B028

B029

B030

B031

B032

B033

B034

B035

B036

B037

B038

B039

B040

B041

B042

B043

B044

B045

B046

B047

B048

B049

B050

B051

B052

B053

B054

B055

B056

B057

B058

B059

B060

B061

B062

B063

B064

B065

B066

B067

B068

B069

B070

B071

B072

B073

B074

B075

B076

B077

B078

B079

B080

B081

B082

B083

B084

B085

B086

B087

B088

B089

B090

B091

B092

B093

B094

B095

B096

B097

B098

B099

B100

B101

B102

B103

B104

B105

B106

B107

B108

B109

B110

B111

B112

B113

B114

B115

B116

B117

B118

B119

B120

B121

B122

B123

B124

B125

B126

B127

B128

B129

B130

B131

B132

B133

B134

B135

B136

B137

B138

B139

B140

Com- pound No. STRUCTURE B141

B142

B143

B144

B145

B146

B147

B148

B149

B150

B151

B152

B153

B154

B155

B156

B157

B158

B159

B160

B161

B162

B163

B164

B165

B166

B167

B168

B169

B170

B171

B172

B173

B174

B175

B176

B177

B178

B179

B180

B181

B182

B183

B184

B185

B186

B187

B188

B189

B190

B191

B192

B193

B194

B195

B196

B197

B198

B199

B200

B201

B202

B203

B205

B206

B207

B208

B209

B213

B214

B215

B216

B217

B218

B219

B220

B221

B222

B223

B224

B225

B226

B227

B228

B229

B230

B231

B232

B233

B234

B235

B236

B237

B238

B239

B240

B241

B242

B243

B244

B245

B246

B247

B248

B249

B250

B251

B252

B253

B254

B255

B256

B257

B258

B259

B260

B261

B262

B263

B264

B265

B266

B267

B268

B269

B270

B271

B272

B273

B274

B275

B276

B277

B278

B279

B280

B281

B282

B283

B284

B285

B286

B287

B288

B289

B290

B291

B292

B293

B294

B295

B296

B297

B298

Com- pound No. STRUCTURE C001

C002

C003

C004

C005

C006

C007

C008

C009

C010

C011

C012

C013

C014

C015

C016

C017

C018

C019

C020

C021

C022

C023

C024

C025

C026

C027

C028

C029

C030

C031

C032

C033

C034

C035

C036

C037

C038

C039

C040

C041

C042

C043

C044

C045

C046

C047

C048

C049

C050

C051

C052

C053

C054

C055

C056

C057

C058

C059

C060

C061

C062

C063

C064

C065

C066

C067

C068

C069

C070

C071

C072

C073

C074

C075

C076

C077

C078

C079

C080

C081

C082

C083

C084

C085

C086

C087

C088

C089

C090

C091

C092

C093

C094

C095

C096

C097

C098

C099

C101

C102

C103

C104

C105

C106

C107

C108

C109

C110

C111

C112

C113

C114

C115

C116

C117

C118

C119

C120

C121

C122

C123

C124

C125

C126

C127

C128

C129

C130

C131

C132

C133

C134

C135

C136

C137

C138

C139

C140

C141

C142

C143

C144

C145

C146

C147

C148

C149

C150

C151

C152

C153

C154

C155

C156

C157

C158

C159

C160

C161

C162

C163

C164

C165

C166

C167

C168

C169

C170

C171

C172

C173

C174

C175

C176

C177

C178

C179

C180

C181

C182

C183

C184

C185

C186

C187

C188

C189

C190

C191

C192

C193

C194

C195

C196

C197

C198

C199

C201

C202

C203

C204

C205

C206

C207

C208

C209

C210

C250

C251

C260

C261

C351

C352

C353

C354

C355

C356

C357

C358

C359

C360

C361

C362

C363

C364

C365

C366

C367

C368

C384

C385

C386

C387

C388

C389

C390

D001

D002

D003

D004

D005

D006

D007

D008

D009

D010

D011

D012

D013

D014

D015

D016

D017

D018

D019

D020

D021

D022

D023

D024

D025

Compound B288 and B289

Measurement condition

-   -   CHIRALPAK AD     -   Mobile phase: n-hexane: i-propanol=80:20     -   Flow rate: 1.0 ml/min     -   Temperature: 30° C.

Retention time

-   -   B288:18.1 min     -   B289:18.6 min         Compound C389 and C390

Measurement condition

-   -   CHIRALPAK AD     -   Mobile phase: n-hexane: i-propanol=60:40     -   Flow rate: 1.0 ml/min     -   Temperature: 30° C.

Retention time

-   -   C389:12.0 min     -   C390:14.7 min

Particularly preferred compounds of the present invention represented by formula (I) include:

-   3-methyl-2-(2-oxo-2-phenylethylamino)-6-pyridin-4-yl-3H-pyrimidin-4-one; -   3-methyl-2-(2-oxo-2-(3-fluorophenyl)ethylamino)-6-pyridin-4-yl-3H-pyrimidin-4-one; -   3-methyl-2-(2-oxo-2-(4-fluorophenyl)ethylamino)-6-pyridin-4-yl-3H-pyrimidin-4-one; -   3-methyl-2-(2-oxo-2-(3-chlorophenyl)ethylamino)-6-pyridin-4-yl-3H-pyrimidin-4-one; -   3-methyl-2-(2-oxo-2-(3-methylphenyl)ethylamino)-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(4-Fluorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   (S-2-[2-(4-Fluorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(2-Fluorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   (S)-2-[2-(2-Fluorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(4-Chlorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(3-Chlorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(2-Chlorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   (S)-2-[2-(2-Chlorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(4-Bromophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   (S3-2-[2-(4-Bromophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(3-Bromophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   (S)-2-[2-(3-Bromophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(2-Bromophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(4-Methylphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(3-Methylphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(2-Methylphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   (S)-2-[2-(2-Methylphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(4-Cyanophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(3-Cyanophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   (S)-2-[2-(3-Cyanophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(2-Cyanophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(4-Methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   (S-2-[2-(4-Methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(3-Methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   (S)-2-[2-(3-Methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(2-Methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   (S)-2-[2-(2-Methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(2-Ethoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(2-Trifluoromethoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(5-Fluoro-2-methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(4-Fluoro-2-methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   (S)-2-[2-(4-Fluoro-2-methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(2,5-Dimethoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   (S)-2-[2-(2,5-Dimethoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(2-Chloro-4,5-difluorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   (S-2-[2-(2-Chloro-4,5-difluorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(2-Bromo-4-fluorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(2,4-Difluorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   (S)-2-[2-(2,4-Difluorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(2,6-Dimethoxyphenyl)morpholin-4-yl]-3-methyl-6-pyrimidin-4-one; -   (S-2-[2-(2,6-Dimethoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(2,4-Dim     ethoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   (S-2-[2-(2,4-Dimethoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(2,6-Dichlorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   (S)-2-[2-(2,6-Dichlorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-o     ne; -   2-[2-(2,6-Difluorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   (S)-2-[2-(2,6-Difluorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(2-Chloro-6-fluorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   (S)-2-[2-(2-Chloro-6-fluorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(4-Fluoro-3-methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(5-Cyano-2-methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   (S)-2-[2-(5-Cyano-2-methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(4-Cyano-2-methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   (S)-2-[2-(4-Cyano-2-methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(2,4-Difluoro-6-methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   (S)-2-[2-(2,4-Difluoro-6-methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(4-(Pyrrolidin-1-yl-methyl)phenyl)morpholino-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   (S-2-[2-(4-(Pyrrolidin-1-yl-methyl)phenyl)morpholino-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(1-Naphthyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(2-Naphthyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   (S-2-[2-(2-Naphthyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(2,3-Dihydrobenzofuran-7-yl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   (S)-2-[2-(2,3-Dihydrobenzofuran-7-yl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(Benzofuran-2-yl)morpholin-4-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   (S)-2-[2-(Benzofuran-2-yl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[3-(4-Fluorobenzoyl)piperidin-1-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-(3-Benzoylpiperidin-1-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[3-(2-Methoxybenzoyl)piperidin-1-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[3-(4-Methoxybenzoyl)piperidin-1-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(4-Fluorobenzoyl)morpholine-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-(2-Benzoylmorpholine-4-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(2-Methoxybenzoyl)morpholine-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[2-(4-Methoxybenzoyl)morpholine-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one -   2-(4-(4-Chlorobenzoyl)piperidin-1-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; -   2-[4-(3,4-Dihydro-2H-quinoline-1-carbonyl)-piperidin-1-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;     and -   2-[4-(2,3-Dihydroindole-1-carbonyl)-piperidin-1-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one.

Salts of the aforementioned preferred compound, and solvates or hydrates of the aforementioned compounds and salts thereof are also preferred.

The 3-substituted-4-pyrimidone compounds represented by the aforementioned formula (I) wherein R is the group represented by formula (II) can be prepared, for example, according to the method explained below.

(In the above scheme, definitions of R¹, R², R³ and R⁴ are the same as those already described.).

The 2-thiopyrimidone represented by the above formula (XI) is prepared easily by a modification of the method described in EP 354,179. The reaction is carried out in the presence of a base such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5,4,0]undec-7-en for 1 to 100 hours at a suitable temperature ranging from 0° C. to 200° C. under nitrogen or argon atmosphere or under ordinary air to afford the desired compound (XI). Examples of a solvent for the reactions include, for example, alcoholic solvent such as methanol, ethanol, 1-propanol, isopropanol, tert-butanol, ethylene glycol, propylene glycol; etheric solvents such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran, isopropyl ether; hydrocarbonic solvents such as benzene, toluene, xylene; halogenated hydrocarbonic solvents such as dichloromethane, chloroform, dichloroethane; aprotic polar solvents such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, hexamethylphosphoric triamide, water and the like. Generally, a single solvent or a mixture of two or more solvents may be used so as to be suitable to a base used.

Then the 2-thiopyrimidone derivative (XI) is transformed into the 2-chloropyrimidone (XII) by a chlorinating agent. The reaction time and temperature depend on the chlorinating agent used. Examples of a chlorinating agent for the reactions include, for example, thionyl chloride, thionyl chloride and dimethylformamide, phosphorus oxychloride, phosphorus oxychloride and dimethylformamide, oxalyl chloride, phosphorous oxychloride and dimethylformamide, and phosphorus pentachloride.

The amine represented by the above formula (XIII) or salts thereof is may be prepared by a modification of the method described in the literature (Tetrahedron Lett., 30, 5285 (1989), Synthesis, 122 (1990)).

Then the chloride derivative (XII) is allowed to react with the amine (XIII) or salts thereof in the presence of a base such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5,4,0]undec-7-en for 1 to 100 hours at a suitable temperature ranging from 0° C. to 200° C. under nitrogen or argon atmosphere or under ordinary air to afford the desired compound (I). 4-Dimethylaminopyridine may be used as a catalyst.

Examples of a solvent for the reactions include, for example, alcoholic solvent such as methanol, ethanol, 1-propanol, isopropanol, tert-butanol, ethylene glycol, propylene glycol; etheric solvents such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran, isopropyl ether; hydrocarbonic solvents such as benzene, toluene, xylene; halogenated hydrocarbonic solvents such as dichloromethane, chloroform, dichloroethane; aprotic polar solvents such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, hexamethylphosphoric triamide, water and the like. Generally, a single solvent or a mixture of two or more solvents may be used so as to be suitable to a base used.

The 3-substituted-4-pyrimidone compounds represented by the aforementioned formula (I) wherein R is the group represented by formula (III) can be prepared, for example, according to the method explained below.

(In the above scheme, definitions of R¹, R⁵, R⁶, R⁷ and R⁸ are the same as those already described.)

The chloride derivative (XII) is allowed to react with the amine (IVX) or salts thereof in the presence of a base such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5,4,0]undec-7-en for 1 to 100 hours at a suitable temperature ranging from 0° C. to 200° C. under nitrogen or argon atmosphere or under ordinary air to afford the desired compound (I).

Examples of a solvent for the reactions include, for example, alcoholic solvent such as methanol, ethanol, 1-propanol, isopropanol, tert-butanol, ethylene glycol, propylene glycol; etheric solvents such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran, isopropyl ether; hydrocarbonic solvents such as benzene, toluene, xylene; halogenated hydrocarbonic solvents such as dichloromethane, chloroform, dichloroethane; aprotic polar solvents such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, hexamethylphosphoric triamide, water and the like. Generally, a single solvent or a mixture of two or more solvents may be used so as to be suitable to a base used.

The 3-substituted-4-pyrimidone compounds represented by the aforementioned formula (I) wherein R is the group represented by formula (IV) can be prepared, for example, according to the method explained below.

(In the above scheme, definitions of R¹, R⁹, and X are the same as those already described.)

The amine represented by the above formula (VX) may be prepared by a modification of the method described in the literature (J. Med. Chem., 13, 1 (1970), J. Med. Chem., 41, 591 (1998)) or according to well-known methods of one skilled in the art.

Then the chloride derivative (XII) is allowed to react with the amine (VX) or salts thereof in the presence of a base such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5,4,0]undec-7-en for 1 to 100 hours at a suitable temperature ranging from 0° C. to 200° C. under nitrogen or argon atmosphere or under ordinary air to afford the desired compound (I).

Examples of a solvent for the reactions include, for example, alcoholic solvent such as methanol, ethanol, 1-propanol, isopropanol, tert-butanol, ethylene glycol, propylene glycol; etheric solvents such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran, isopropyl ether; hydrocarbonic solvents such as benzene, toluene, xylene; halogenated hydrocarbonic solvents such as dichloromethane, chloroform, dichloroethane; aprotic polar solvents such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, hexamethylphosphoric triamide, water and the like. Generally, a single solvent or a mixture of two or more solvents may be used so as to be suitable to a base used.

The 3-substituted-4-pyrimidone compounds represented by the aforementioned formula (I) wherein R is the group represented by formula (V) can be prepared, for example, according to the method explained below.

(In the above scheme, definitions of R¹ and R¹⁰ are the same as those already described.).

The amine represented by the above formula (VIX) is commercially available or may be prepared by a modification of the method described in the literature (J. Med. Chem., 13, 1 (1970), J. Med. Chem., 41, 591 (1998)) or according to well-known methods of one skilled in the art.

Then the chloride derivative (XII) is allowed to react with the amine (VIX) or salts thereof in the presence of a base such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5,4,0]undec-7-en for 1 to 100 hours at a suitable temperature ranging from 0° C. to 200° C. under nitrogen or argon atmosphere or under ordinary air to afford the desired compound (I).

Examples of a solvent for the reactions include, for example, alcoholic solvent such as methanol, ethanol, 1-propanol, isopropanol, tert-butanol, ethylene glycol, propylene glycol; etheric solvents such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran, isopropyl ether; hydrocarbonic solvents such as benzene, toluene, xylene; halogenated hydrocarbonic solvents such as dichloromethane, chloroform, dichloroethane; aprotic polar solvents such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, hexamethylphosphoric triamide, water and the like. Generally, a single solvent or a mixture of two or more solvents may be used so as to be suitable to A base used.

The compounds of the present invention have inhibitory activity against TPK1, and they inhibit TPK1 activity in neurodegenerative diseases such as Alzheimer disease, thereby suppress the neurotoxicity of A β and the formation of PHF and inhibit the nerve cell death. Accordingly, the compounds of the present invention are useful as an active ingredient of a medicament which radically enables preventive and/or therapeutic treatment of Alzheimer disease. In addition, the compounds of the present invention are also useful as an active ingredient of a medicament for preventive and/or therapeutic treatment of ischemic cerebrovascular accidents, Down syndrome, cerebral bleeding due to solitary cerebral amyloid angiopathy, progressive supranuclear palsy, subacute sclerosing panencephalitis, postencephalitic parkinsonism, pugilistic encephalosis, Guam parkinsonism-dementia complex, Lewy body disease, Pick's disease, corticobasal degeneration frontotemporal dementia, vascular dementia, traumatic injuries, brain and spinal cord trauma, peripheral neuropathies, retinopathies and glaucoma, non-insulin dependent diabetes, obesity, manic depressive illness, schizophrenia, alopecia, breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia, and several virus-induced tumors.

As the active ingredient of the medicament of the present invention, a substance may be used which is selected from the group consisting of the compound represented by the aforementioned formula (I) and pharmacologically acceptable salts thereof, and solvates thereof and hydrates thereof. The substance, per se, may be administered as the medicament of the present invention, however, it is desirable to administer the medicament in a form of a pharmaceutical composition which comprises the aforementioned substance as an active ingredient and one or more of pharmaceutical additives. As the active ingredient of the medicament of the present invention, two or more of the aforementioned substance may be used in combination. The above pharmaceutical composition may be supplemented with an active ingredient of other medicament for the treatment of Alzheimer disease and the above-mentioned diseases.

A type of the pharmaceutical composition is not particularly limited, and the composition may be provided as any formulation for oral or parenteral administration. For example, the pharmaceutical composition may be formulated, for example, in the form of pharmaceutical compositions for oral administration such as granules, fine granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions, solutions and the like, or in the form of pharmaceutical compositions for parenteral administrations such as injections for intravenous, intramuscular, or subcutaneous administration, drip infusions, transdermal preparations, transmucosal preparations, nasal drops, inhalants, suppositories and the like. Injections or drip infusions may be prepared as powdery preparations such as in the form of lyophilized preparations, and may be used by dissolving just before use in an appropriate aqueous medium such as physiological saline. Sustained-release preparations such as those coated with a polymer may be directly administered intracerebrally.

Types of pharmaceutical additives used for the manufacture of the pharmaceutical composition, content rations of the pharmaceutical additives relative to the active ingredient, and methods for preparing the pharmaceutical composition may be appropriately chosen by those skilled in the art. Inorganic or organic substances, or solid or liquid substances may be used as pharmaceutical additives. Generally, the pharmaceutical additives may be incorporated in a ratio ranging from 1% by weight to 90% by weight based on the weight of an active ingredient.

Examples of excipients used for the preparation of solid pharmaceutical compositions include, for example, lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate and the like. For the preparation of liquid compositions for oral administration, a conventional inert diluent such as water or a vegetable oil may be used. The liquid composition may contain, in addition to the inert diluent, auxiliaries such as moistening agents, suspension aids, sweeteners, aromatics, colorants, and preservatives. The liquid composition may be filled in capsules made of an absorbable material such as gelatin. Examples of solvents or suspension mediums used for the preparation of compositions for parenteral administration, e.g. injections, suppositories, include water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin and the like. Examples of base materials used for suppositories include, for example, cacao butter, emulsified cacao butter, lauric lipid, witepsol.

Dose and frequency of administration of the medicament of the present invention are not particularly limited, and they may be appropriately chosen depending on conditions such as a purpose of preventive and/or therapeutic treatment, a type of a disease, the body weight or age of a patient, severity of a disease and the like. Generally, a daily dose for oral administration to an adult may be 0.01 to 1,000 mg (the weight of an active ingredient), and the dose may be administered once a day or several times a day as divided portions, or once in several days. When the medicament is used as an injection, administrations may preferably be performed continuously or intermittently in a daily dose of 0.001 to 100 mg (the weight of an active ingredient) to an adult.

EXAMPLES

The present invention will be explained more specifically with reference to examples. However, the scope of the present invention is not limited to the following examples. The compound number in the examples corresponds to that in the table above.

Example 1 Synthesis of 2-mercapto-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one

A solution of ethyl 3-oxo-3-(4-pyridyl)propionate (29.0 g, 150 mmol), N-methyl thiourea (40.6 g, 450 mmol) and 1,8-diazabicyclo[5,4,0]-7-undecene (22.4 ml, 150 mmol) was refluxed for 4 hours and the solution of methanesulfonic acid (14.4 g, 150 mmol) in water (50 ml) was added after cooling by ice-water. The precipitate was washed with water, filtered and dried to give the title compound (23.7 g, 72%).

¹H-NMR (DMSO-d₆) δ: 3.58 (s, 3H), 6.40 (s, 1H), 7.72 (dd, J=1.8, 4.5 Hz, 2H), 8.73 (dd, J=1.5, 4.8 Hz, 2H), 12.92 (brd, 1H).

Example 2 Synthesis of 2-chloro-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one

Phosphorous oxychloride (26.11 g, 170 mmol) was added to dimethylformamide (180 ml) and stirred 20 min. 2-mercapto-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (24.15 g, 110 mmol) was added to the solution and stirred 5 min and then stirred at 70° C. for 2 hours. Ethyl acetate (630 ml) was added to the ice-cooled solution and precipitate was collected by filtration after 20 minutes stirring. After drying, the precipitate was dissolved in water (400 ml) and pH was adjusted to 10 by aqueous sodium hydroxide. The precipitate was washed with water, filtered and dried to give the title compound (18.82 g, 77%).

¹H-NMR (CDCl₃) δ: 3.72 (s, 3H), 6.90 (s, 1H), 7.78 (dd, J=1.7, 4.5 Hz, 2H), 8.75 (dd, J=1.6, 4.5 Hz, 2H).

Example 3 Synthesis of 3-methyl-2-(2-oxo-2-phenylethylamino)-6-pyridin-4-yl-3H-pyrimidin-4-one (Compound No. A001 in Table-1)

A solution of 2-amino-1-phenyl-ethanone hydrochloride (1.03 g, 6.00 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (0.665 g, 3.00 mmol), 4-dimethylaminopiridine (36.0 mg, 0.30 mmol) and triethylamine (0.80 ml, 6.00 mmol) in dimethylsulfoxide (15 ml) was stirred at room temperature. After stirring for several hours, water was added to the reaction mixture. The precipitate was filtered and washed with refluxing diethyl ether to give the title compound (0.556 g, 68%).

¹H-NMR (CDCl₃) δ: 3.41 (s, 3H), 4.90 (d, J=5.1 Hz, 2H), 6.46 (s, 1H), 7.50-7.65 (m, 2H), 7.67-7.80 (m, 3H), 7.90 (t, J=5.1 Hz, 1H), 8.08 (m, 2H), 8.47 (dd, J=1.5 Hz, 4.8 Hz, 2H). MS[M+H]⁺: 321.

Example 4 Synthesis of (S)-2-[2-(4-Methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (Compound No. B079 in Table-1).

A solution of (S)-2-(4-methoxyphenyl)morpholine hydrochloride (1.02 g, 4.44 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (0.76 g, 3.42 mmol) and triethylamine (1.42 ml, 10.3 mmol) in tetrahydrofuran (20 ml) was refluxed for several hours. The precipitate was filtered off after cooling and solvent was removed in vacuo. The residue was washed with refluxing diethyl ether to give the title compound (1.22 g, 95%).

¹H-NMR (DMSO-d₆) δ: 2.98-3.06 (m, 1H), 3.15-3.22 (m, 1H), 3.47 (s, 3H), 3.69-3.73 (m, 2H), 3.76 (s, 3H), 3.85-3.92 (m, 1H), 4.04-4.08 (m, 1H), 4.67-4.70 (m, 1H), 6.95 (d, J=8.5 Hz, 2H), 7.10 (s, 1H), 7.38 (d, J=8.5 Hz, 2H), 8.49 (d, J=6.0 Hz, 2H), 8.94 (d, J=6.0 Hz, 2H).

MS[M+H]⁺: 379

Example 5 Synthesis of 2-[2,2-Dimethyl-6-(4-Fluorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (Compound No. B214 in Table-1)

A solution of 2,2-dimethyl-6-(4-fluorophenyl)morpholine hydrochloride (127 mg, 0.517 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (109 mg, 0.491 mmol) and triethylamine (0.180 ml, 1.29 mmol) in N,N-dimethylformamide (2 ml) was stirred at room temperature. After stirring for several hours, water was added to the reaction mixture. The precipitate was filtered, washed with water and dried to give the title compound (166 mg, 81%).

¹H-NMR (CDCl₃) δ: 1.39 (s, 3H), 1.51 (s, 3H), 2.86-3.02 (m, 2H), 3.39 (m, 1H), 3.60 (s, 3H), 3.65 (m, 1H), 5.04 (m, 1H), 6.69 (s, 1H), 7.09 (m, 2H), 7.42 (m, 2H), 7.79 (d, J=6.0 Hz, 2H), 8.72 (d, J=6.0 Hz, 2H).

MS[M+H]⁺: 394

Example 6 Synthesis of 2-(3-Benzoylpiperidin-1-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (Compound No. C001 in Table-1).

A solution of 3-benzoylpiperidine hydrochloride (109 mg, 0.60 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (118 mg, 0.40 mmol) and triethylamine (0.50 ml, 4.00 mmol) in tetrahydrofuran (6 ml) was stirred at room temperature for several hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄ and evaporated in vacuo. Purification of the residue by silica gel column chromatography (ethyl acetate) gave the title compound (182 mg, 61%).

Example 7 Synthesis of 1-(1-Methyl-6-oxo-4-pyridin-4-yl-1,6-dihydro-pyrimidine-2-yl)-piperidine-3-carboxanilide (Compound No. CO₆₇ in Table-1)

A solution of 1-t-butoxycarbonyl-3-piperidinecarboxylic acid (458 mg, 2.00 mmol), sodium hydride (88 mg, 2.20 mmol, 60% oil suspension), oxalyl chloride (0.22 ml, 2.50 mmol) and catalytic amount of dimethylformamide (0.20 ml) in dichloromethane (16 ml) was stirred at 0° C. After stirring for 30 min, aniline (0.20 ml, 2.20 mmol) which was treated with n-butyl lithium (1.45 ml, 2.30 mmol, 1.59 M in hexane) in tetrahydrofuran (4 ml) was added to the reaction mixture at 0° C. After additional 30 min, saturated ammonium hydrochloride was added and the whole reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄ and evaporated in vacuo. Purification of the residue by silica gel column chromatography (hexane-ethyl acetate) gave 1-t-butoxycarbonylpiperidine-3-carboxanilide (437 mg, 71%).

A solution of 1-t-butoxycarbonyl-3-piperidinecarboxanilide (437 mg, 1.43 mmol) and hydrochloride (1 ml, 4.00 mmol, 4N ethyl acetate) was stirred for several hours. Filtration of the precipitate gave 3-piperidinecarboxanilide hydrochloride (187 mg, 55%).

A solution of 3-piperidinecarboxanilide hydrochloride (96.0 mg, 0.40 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (66.0 mg, 0.30 mmol) and triethylamine (0.33 ml, 2.50 mmol) in tetrahydrofuran (3 ml) was stirred at room temperature for 3 hours. The whole reaction mixture was evaporated in vacuo and the precipitate was washed with water and diethyl ether to give the title compound (107 mg, 92%).

Example 8 Synthesis of 2-(2-benzoylmorpholin-4-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (Compound No. C101 in Table-1)

Grignard's reagent was prepared by reaction of magnesium (932 mg, 5.93 mmol) with bromobenzene (144 mg, 5.93 mmol) in diethyl ether (20 ml) at room temperature for 10 min. After cooling to 0° C., a solution of 2-cyano-4-benzyl-morpholine (1.00 g, 4.94 mmol) in diethyl ether (2.0 ml) was added and then tetrahydrofuran (6.0 ml) was added. The mixture was stirred at room temperature for 30 min. After decomposition with saturated aqueous sodium hydrogen carbonate, the mixture was filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (n-hexane-ethyl acetate 3:1 to 2:1) to give the 2-benzoyl-4-benzylmorpholine (608 mg, 44%).

(CDCl₃): 2.20-2.40 (m, 2H), 2.60-2.80 (m, 1H), 3.00-3.20 (m, 1H), 3.55 (dd, J=13.0, 27.8 Hz, 2H), 3.70-3.90 (m, 1H), 3.90-4.20 (m, 1H), 4.92 (dd, J=2.6, 9.9 Hz, 1H), 7.20-7.60 (m, 8H), 7.80-8.00 (m, 2H).

A solution of 2-benzoyl-4-benzylmorpholine (600 mg, 2.13 mmol) and chloroformic acid 1-chloromethyl ester (457 mg, 3.20 mmol) in 1,2-dichloroethane (8.0 ml) was refluxed for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (10 ml). The solution was refluxed for 1 h and concentrated under reduced pressure. The crude product was crystallized from ethyl acetate and filtrated to give 2-benzoylmorpholine hydrochloride (323 mg, 67%) as a colorless crystal.

(DMSO-d₆): 3.00-3.50 (m, 4H), 4.00-4.20 (m, 2H), 5.29 (dd, J=2.6, 10.1 Hz, 1H), 7.50-8.10 (m, 5H), 9.40-9.90 (brd, 2H).

A solution of 2-benzoylmorpholine hydrochloride (269 mg, 1.17 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (320 mg, 1.41 mmol) and triethylamine (0.49 ml, 3.51 mmol) in tetrahydrofuran (10 ml) was refluxed for several hours. The precipitate was filtered off after cooling and solvent was removed in vacuo. The residue was washed with refluxing ethyl acetate and diethyl ether to give the title compound (447 mg, quant.).

Example 9 Synthesis of 2-(4-benzoylpiperidin-1-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (Compound No. D001 in Table-1)

A solution of 4-benzoylpiperidine hydrochloride (903 mg, 4.00 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (666 mg, 3.00 mmol) and triethylamine (2.0 ml, 15 mmol) in tetrahydrofuran (30 ml) was refluxed for several hours. After cooling, water was added to the reaction mixture. The precipitate was filtered, washed with water and dried to give the title compound (1.00 g, 81%).

Example 10 Synthesis of 2-[4-(4-Chlorobenzoyl)piperidin-1-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (Compound No. D009 in Table-1)

A solution of (4-Chlorobenzoyl)piperidine hydrochloride (55 mg, 0.226 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (50 mg, 0.226 mmol) and triethylamine (0.160 ml, 1.15 mmol) in N,N-dimethylformamide (1 ml) was stirred at 60° C. After stirring for several hours, water was added to the reaction mixture. The precipitate was filtered, washed with water and dried to give the title compound (76 mg, 86%).

The compounds in the following table were prepared in the same manner as the methods described above. The compound numbers in the following table correspond to those shown in the above-described table of preferred compounds. TABLE 2 Compound No. ¹H-NMR(Solvent) δ: [M+H]+ A002 (CDCl₃): 3.59(s, 3H), 5.00(dd, J=3.8, 3.8Hz, 2H), 6.19(brs, 1H), 339 6.50(s, 1H), 7.24-7.37(m, 2H), 7.67(m, 1H), 7.78(d, J=5.1Hz, 2H), 8.04(m, 1H), 8.68(d, J=5.1Hz, 2H). A003 (CDCl₃): 3.60(s, 3H), 5.02(d, J=3.9Hz, 2H), 6.06(brs, 1H), 338 6.50(s, 1H), 7.26-7.88(m, 6H), 7.71(d, J=5.4Hz, 2H). A004 (CDCl₃): 3.41(s, 3H), 4.89(s, 2H), 6.48(s, 1H), 7.42(m, 2H), 339 7.70(dd, J=1.5Hz, 4.5Hz, 2H), 7.92(br, 1H), 8.18(m, 2H), 8.49(dd, J=1.5Hz, 4.5Hz, 2H). A006 (DMSO): 3.39(s, 3H), 4.88(d, J=5.1Hz, 2H), 6.46(s, 1H), 355 7.58-8.08(m, 6H), 7.67(m, 1H), 8.48(d, J=5.1Hz, 2H). A012 (CDCl₃): 2.48(s, 3H), 3.60(s, 3H), 5.01(d, J=3.9Hz, 2H), 355 6.22(brs, 1H), 6.48(s, 1H), 7.43-7.49(m, 2H), 7.79(dd, J=4.5, 1.8Hz, 2H), 7.86-7.89(m, 2H), 8.67(dd, J=4.5, 1.8Hz, 2H). B008 (CDCl₃): 0.99(s, 9H), 2.89(m, 1H), 3.10-3.65(m, 4H), 3.53(s, 328 3H), 3.76(m, 1H), 4.04(m, 1H), 6.68(s, 1H), 7.80(d, J=6.0Hz, 2H), 8.72(d, J=6.0Hz, 2H). B009 (CDCl₃): 2.74(dd, J=13.7, 7.4Hz, 1H), 2.87(dd, J=12.7, 363 10.4Hz, 1H), 3.02(dd, J=13.7, 6.2Hz, 1H), 3.24(td, J=12.2, 3.0Hz, 1H), 3.39(s, 3H), 3.48(dd, J=15.1, 1.6Hz, 2H), 3.77(td, J=11.7, 2.4Hz, 2H), 3.91(m, 1H), 4.03(dd, J=11.6, 2.0Hz, 1H), 6.65(s, 1H), 7.24-7.37(m, 5H), 7.71(dd, J=6.0, 1.5Hz, 2H), 8.70(dd, J=6.0, 1.5Hz, 2H). B010 (CDCl₃): 1.81(m, 1H), 1.93(m, 1H), 2.76(m, 1H), 2.89(m, 1H), 377 3.19(td, J=11.6, 3.1Hz, 1H), 3.44(m, 2H), 3.49(s, 3H), 3.65(m, 1H), 3.81(td, J=11.5, 2.0Hz, 1H), 4.06(dt, J=10.7, 1.1Hz, 1H), 6.68(s, 1H), 7.21-7.34(m, 5H), 7.77(dd, J=4.6, 1.5Hz, 2H), 8.73(dd, J=4.6, 1.5Hz, 2H). B011 (CDCl₃): 1.49-1.90(m, 4H), 2.67(d, J=7.2Hz, 2H), 2.83(dd, J=12.8, 391 10.5Hz, 1H), 3.15(td, J=11.9, 2.8Hz, 1H), 3.45(d, J=12.8Hz, 2H), 3.52(s, 3H), 3.65(m, 1H), 3.79(dd, J=11.4, 2.1Hz, 1H), 4.01(dd, J=11.1, 1.5Hz, 1H), 6.68(s, 1H), 7.18-7.33(m, 5H), 7.79(dd, J=4.5, 1.5Hz, 2H), 8.71(dd, J=4.8, 1.5Hz, 2H). B012 (CDCl₃): 3.10-3.33(m, 2H), 3.50(m, 1H), 3.71-4.20(m, 6H), 378 6.70(s, 1H), 6.89-7.03(m, 3H), 7.24-7.36(m, 2H), 7.80(d, J=6.0Hz, 2H), 8.71(d, J=6.0Hz, 2H). B027 (DMSO-d₆): 3.01(m, 1H), 3.15(m, 1H), 3.47(s, 3H), 3.73(dd, 349 J=13.5, 13.5Hz, 2H), 3.90(dd, J=10.9, 10.9Hz, 1H), 4.07(d, J=11.0Hz, 1H), 4.74(d, J=9.3Hz, 1H), 7.06(s, 1H), 7.30-7.47(m, 5H), 8.40(d, J=6.3Hz, 2H), 8.90(d, J=6.3Hz, 2H). B028 (DMSO-d₆): 3.01(m, 1H), 3.15(m, 1H), 3.47(s, 3H), 3.73(dd, 349 J=13.4, 13.4Hz, 2H), 3.90(dd, J=11.6, 11.6Hz, 1H), 4.07(d, J=10.1Hz, 1H), 4.74(d, J=9.3Hz, 1H), 7.07(s, 1H), 7.30-7.46(m, 5H), 8.43(d, J=6.3Hz, 2H), 8.92(d, J=6.3Hz, 2H). B029 (DMSO-d₆): 3.02(m, 1H), 3.15(m, 1H), 3.47(s, 3H), 3.74(dd, 349 J=13.4, 13.4Hz, 2H), 3.90(dd, J=11.7, 11.7Hz, 1H), 4.07(d, J=11.2Hz, 1H), 4.74(d, J=9.3Hz, 1H), 7.07(s, 1H), 7.30-7.47(m, 5H), 8.44(d, J=6.3Hz, 2H), 8.92(d, J=6.3Hz, 2H). B030 (DMSO-d₆): 3.00(dd, J=12.9, 10.8, 1H), 3.18(m, 1H), 3.47(s, 367 3H), 3.73(dd, J=12.3, 12.3Hz, 2H), 3.89(dd, J=9.9, 9.9Hz, 1H), 4.07(d, J=11.2Hz, 1H), 4.75(d, J=9.3Hz, 1H), 7.04(s, 1H), 7.18-7.24(m, 2H), 7.47-7.52(m, 2H), 8.40(d, J=6.6Hz, 2H), 8.90(d, J=6.6Hz, 2H). B031 (DMSO-d₆): 3.01(dd, J=12.9, 10.8, 1H), 3.18(m, 1H), 3.47(s, 367 3H), 3.74(dd, J=12.0, 12.0Hz, 2H), 3.91(dd, J=11.7, 11.7Hz, 1H), 4.08(d, J=10.5Hz, 1H), 4.75(d, J=9.3Hz, 1H), 7.05(s, 1H), 7.19-7.26(m, 2H), 7.48-7.54(m, 2H), 8.38(d, J=6.3Hz, 2H), 8.90(d, J=6.3Hz, 2H). B032 (DMSO-d₆): 3.01(dd, J=12.9, 10.8, 1H), 3.19(m, 1H), 3.47(s, 367 3H), 3.73(dd, J=11.4, 11.4Hz, 2H), 3.91(dd, J=11.4, 11.4Hz, 1H), 4.08(d, J=11.4Hz, 1H), 4.75(d, J=9.3Hz, 1H), 7.04(s, 1H), 7.19-7.26(m, 2H), 7.48-7.54(m, 2H), 8.36(d, J=6.3Hz, 2H), 8.89(d, J=6.3Hz, 2H). B033 (DMSO-d₆): 3.00(m, 1H), 3.18(m, 1H), 3.47(s, 3H), 3.73-4.10 367 (m, 4H), 4.77(d, J=9.4Hz, 1H), 7.05(s, 1H), 7.13-7.48(m, 4H), 8.38(d, J=6.0Hz, 2H), 8.89(d, J=6.0Hz, 2H). B036 (DMSO-d₆): 3.06(m, 1H), 3.22(m, 1H), 3.47(s, 3H), 3.68-4.11 367 (m, 4H), 5.05(d, J=9.3Hz, 1H), 7.06(s, 1H), 7.22-7.61(m, 4H), 8.40(d, J=6.3Hz, 2H), 8.90(d, J=6.3Hz, 2H). B037 (DMSO-d₆): 3.04(m, 1H), 3.23(m, 1H), 3.46(s, 3H), 3.66-4.09 367 (m, 4H), 5.04(d, J=9.6Hz, 1H), 7.05(s, 1H), 7.20-7.59(m, 4H), 8.39(d, J=6.0Hz, 2H), 8.88(d, J=6.0Hz, 2H). B038 (DMSO-d₆): 3.07(m, 1H), 3.24(m, 1H), 3.48(s, 3H), 3.69-4.10 367 (m, 4H), 5.05(d, J=9.3Hz, 1H), 7.10(s, 1H), 7.21-7.61(m, 4H), 8.49(d, J=6.3Hz, 2H), 8.94(d, J=6.3Hz, 2H). B039 (DMSO-d₆): 2.97(dd, J=11.0, 12.6Hz, 1H), 3.12-3.20(m, 1H), 383 3.45(s, 3H), 3.68-3.77(m, 2H), 3.85-3.92(m, 1H), 3.99-4.08(m, 1H), 4.73-4.76(m, 1H), 7.08(s, 1H), 7.42-7.49(m, 4H), 8.47(d, J=5.7Hz, 2H), 8.93(d, J=5.9Hz, 2H). B042 (DMSO-d₆): 3.02(dd, J=12.5, 10.9, 1H), 3.19(m, 1H), 3.48(s, 383 3H), 3.71-4.11(m, 4H), 4.78(d, J=8.9Hz, 1H), 7.08(s, 1H), 7.38-7.53(m, 4H), 8.44(d, J=6.3Hz, 2H), 8.92(d, J=6.3Hz, 2H). B045 (DMSO-d₆): 2.93(dd, J=12.8, 10.6, 1H), 3.23(m, 1H), 3.39(s, 383 3H), 3.69-4.15(m, 4H), 5.06(d, J=9.0Hz, 1H), 7.14(s, 1H), 7.38-7.66(m, 4H), 8.56(d, J=6.3Hz, 2H), 8.98(d, J=6.3Hz, 2H). B046 (DMSO-d₆): 2.89(m, 1H), 3.35(m, 1H), 3.50(s, 3H), 382 3.68-4.14(m, 4H), 5.06(m, 1H), 7.08(s, 1H), 7.39-7.64(m, 4H), 8.46(d, J=5.5Hz, 2H), 8.93(d, J=5.5Hz, 2H). B048 □(DMSO-d₆): 2.96(1H, dd, J=10.7, 12.7Hz), 3.12-3.20(1H, m), [M+]=427 3.45(3H, s), 3.66-3.75(2H, m), 3.86-3.93(1H, m), 4.05-4.09(1H, m), 4.75(1H, d, J=8.9Hz), 6.85(1H, s), 7.42(2H, d, J=8.4Hz), 7.58(2H, d, J=8.3Hz), 7.97(2H, d, J=6.0Hz), 8.69(2H, d, J=6.0Hz) B051 (DMSO-d₆): 2.94-3.02(1H, m), 3.14-3.22(1H, m), 3.46(3H, s), 427 3.66-3.77(2H, m), 3.87-3.94(1H, m), 4.04-4.09(1H, m), 4.76(1H, d, J=9.5Hz), 6.85(1H, s), 7.33-7.38(1H, m), 7.46-7.48(1H, m), 7.52-7.55(1H, m), 7.61-7.70(1H, m), 7.97(2H, d, J=5.7Hz), 8.68(2H, d, J=5.7Hz) B054 (DMSO-d₆): 2.90(dd, J=12.6, 10.5, 1H), 3.22(m, 1H), 3.51(s, 427 3H), 3.67-4.15(m, 4H), 4.98(d, J=9.0Hz, 1H), 7.07(s, 1H), 7.29-7.68(m, 4H), 8.42(d, J=6.3Hz, 2H), 8.90(d, J=6.3Hz, 2H). B057 (DMSO-d₆): 3.00(dd, J=12.6, 10.5, 1H), 3.18(m, 1H), 3.47(s, 363 3H), 3.69-4.09(m, 4H), 4.70(d, J=9.3Hz, 1H), 7.06(s, 1H), 7.20(d, J=7.8Hz, 2H), 7.34(d, J=7.8Hz, 2H), 8.41(d, J=6.3Hz, 2H), 8.91(d, J=6.3Hz, 2H). B060 (DMSO-d₆): 2.33(s, 3H), 2.97-3.05(m, 1H), 3.15-3.22(m, 1H), 363 3.48(s, 3H), 3.70-3.77(m, 1H), 3.86-3.94(m, 1H), 4.05-4.09(m, 1H), 4.69-4.72(m, 1H), 7.07(s, 1H), 7.13-7.28(m, 4H), 8.43(d, J=6.0Hz, 2H), 8.92(d, J=6.3Hz, 2H). B063 (CDCl₃): 2.41(s, 3H), 3.08(m, 1H), 3.35(m, 1H), 3.54(m, 1H), 363 3.59(s, 3H), 3.66(m, 1H), 4.00(m, 1H), 4.21(m, 1H), 4.92(m, 1H), 6.69(s, 1H), 7.18-7.29(m, 3H), 7.55(m, 1H), 7.79(d, J=5.5Hz, 2H), 8.71(d, J=5.5Hz, 2H). B064 (CDCl₃): 2.41(s, 3H), 3.08(m, 1H), 3.35(m, 1H), 3.52-3.69(m, 362 2H), 3.60(s, 3H), 4.00(m, 1H), 4.21(m, 1H), 4.92(m, 1H), 6.69(s, 1H), 7.18-7.29(m, 3H), 7.53(m, 1H), 7.79(d, J=6.3Hz, 2H), 8.70(d, J=6.0Hz, 2H). B066 (DMSO-d₆): 3.11(dd, J=10.8, 12.8Hz, 1H), 3.24-3.32(m, 1H), 417 3.47(s, 3H), 3.68-3.75(m, 2H), 3.90-3.98(m, 1H), 4.10-4.14(m, 1H), 4.96-4.99(m, 1H), 7.11(s, 1H), 7.60(t, J=7.4Hz, 1H), 7.77-7.79(m, 2H), 7.90(d, J=8.0Hz, 1H), 8.48(d, J=6.0Hz, 2H), 8.94(d, J=6.1Hz, 2H). B069 (DMSO-d₆): 3.04(m, 1H), 3.19(m, 1H), 3.48(s, 3H), 3.50-4.15(m, 374 4H), 4.87(d, J=8.7Hz, 1H), 7.04(s, 1H), 7.67(d, J=8.1Hz, 2H), 7.88(d, J=8.1Hz, 2H), 8.35(d, J=6.6Hz, 2H), 8.88(d, J=6.6Hz, 2H). B072 (DMSO-d₆): 3.02(m, 1H), 3.20(m, 1H), 3.49(s, 3H), 3.74(d, 374 J=13.2Hz, 2H), 3.82(d, J=12.3Hz, 2H), 3.94(m, 1H), 4.11(d, J=11.1Hz, 1H), 4.83(d, J=9.9Hz, 2H), 7.08(s, 1H), 7.62(t, J=7.8Hz, 1H), 7.82(d, J=7.8Hz, 2H), 7.92(s, 1H), 8.43(d, J=5.7Hz, 2H), 8.92(d, J=5.7Hz, 2H). B073 (DMSO-d₆): 3.06(m, 1H), 3.12-3.85(m, 6H), 3.94(m, 1H), 373 4.11(d, J=9.9Hz, 1H), 4.83(d, J=9.0Hz, 1H), 7.00(s, 1H), 7.62(m, 1H), 7.83(d, J=7.8Hz, 2H), 7.92(s, 1H), 8.27(d, J=5.4Hz, 2H), 8.84(d, J=5.4Hz, 2H). B075 (DMSO-d₆): 3.09(m, 1H), 3.19-3.33(m, 1H), 3.49(s, 3H), 3.69(d, 373 J=12.6Hz, 1H), 3.83(d, J=12.6Hz, 1H), 3.97(m, 1H), 4.12(d, J=11.7Hz, 1H), 5.02(dd, J=2.4Hz, 10.5Hz, 1H), 6.86(s, 1H), 7.58(m, 1H), 7.73-7.82(m, 2H), 7.90(d, J=7.5Hz, 1H), 7.99(dd, J=1.5Hz, 6.0Hz, 2H), 8.67(dd, J=1.5Hz, 6.0Hz, 2H). B078 (DMSO-d₆): 3.01(m, 1H), 3.18(m, 1H), 3.47(s, 3H), 379 3.68-3.73(m, 2H), 3.75(s, 3H), 3.88(m, 1H), 4.06(m, 1H), 4.68(d, J=9.6Hz, 1H), 6.94(d, J=8.4Hz, 2H), 7.09(s, 1H), 7.37(d, J=8.4Hz, 2H), 8.46(d, J=6.0Hz, 2H), 8.94(d, J=6.0Hz, 2H). B080 (DMSO-d₆): 2.95-3.03(m, 1H), 3.12-3.20(m, 1H), 3.45(s, 3H), 379 3.67-3.71(m, 2H), 3.73(s, 3H), 3.82-3.90(m, 1H), 4.02-4.05(m, 1H), 4.64-4.67(m, 1H), 6.92(d, J=8.5Hz, 2H), 7.08(s, 1H), 7.35(d, J=8.5Hz, 2H), 8.49(d, J=6.2Hz, 2H), 8.96(d, J=6.0Hz, 2H). B081 (DMSO-d₆): 3.02(m, 1H), 3.15(m, 1H), 3.48(s, 3H), 379 3.70-3.75(m, 2H), 3.77(s, 3H), 3.90(m, 1H), 4.08(m, 1H), 4.73(d, J=9.6Hz, 1H), 6.89-7.04(m, 3H), 7.10(s, 1H), 7.31(m, 1H), 8.47(d, J=5.7Hz, 2H), 8.94(d, J=5.7Hz, 2H). B082 (DMSO-d₆): 2.99-3.06(m, 1H), 3.16-3.23(m, 1H), 3.48(s, 3H), 378 3.70-3.74(m, 2H), 3.77(s, 3H), 3.86-3.94(m, 1H), 4.07-4.10(m, 1H), 4.71-4.74(m, 1H), 6.89-6.92(m, 1H), 7.01(s, 1H), 7.06(m, 2H), 7.31(t, J=7.8Hz, 1H), 8.45(d, J=5.9Hz, 2H), 8.93(d, J=5.9Hz, 2H). B084 (DMSO-d₆): 2.82(dd, J=10.2, 12.8Hz, 1H), 3.17-3.26(m, 1H), 379 3.50(s, 3H), 3.68-3.72(m, 1H), 3.83(s, 3H), 3.83-3.94(m, 2H), 4.09-4.13(m, 1H), 5.00-5.03(m, 1H), 6.98-7.07(m, 2H), 7.14(s, 1H), 7.29-7.35(m, 1H), 7.45(d, J=7.4Hz, 1H), 8.59(d, J=6.4Hz, 2H), 9.00(d, J=6.4Hz, 2H). B085 (CDCl₃): 2.83(1H, dd, J=10.2, 12.9Hz), 3..3-3.4(1H, m), 3.5-3.6(1H, 379 m), 3.62(3H, s), 3.8-3.9(1H, m), 3.86(3H, m), 4.0-4.1(1H, m), 4.2-4.3( 1H, m), 5.08(1H, dd, J=2.1, 10.2Hz), 6.69(1H, s), 7.0-7.1(1H, m), 7.2-7.3 (1H, m), 7.53(1H, dd, J=1.5, 7.8Hz), 7.82(1H, dd, J=1.5, 4.5Hz), 8.71 (2H, dd, 1.5, 4.5Hz) B087 (DMSO-d₆): 1.30(3H, t, J=6.8Hz), 2.75(1H, dd, J=10.6, 12.5Hz), 393 3.17-3.25(1H, m), 3.48(3H, s), 3.66-3.71(1H, m), 3.77-3.81(1H, m), 3.89-3.96(1H, m), 4.01-4.13(3H, m), 4.96(1H, d, J=9.3Hz), 6.84(1H, s), 6.95-7.03(2H, m), 7.25-7.31(1H, m), 7.42-7.44(1H, m), 7.98(2H, d, J=5.1Hz), 8.68(2H, d, J=5.3Hz) B088 (CDCl₃): 2.90(m, 1H), 3.35(m, 1H), 3.55(m, 1H), 3.62(s, 3H), 433 3.69(m, 1H), 4.03(m, 1H), 4.24(m, 1H), 5.05(m, 1H), 6.71(s, 1H), 7.26-7.40(m, 3H), 7.68(m, 1H), 7.80(d, J=6.0Hz, 2H), 8.71(d, J=6.0Hz, 2H). B089 (CDCl₃): 2.80(m, 1H), 3.37(m, 1H), 3.53-3.73(m, 2H), 3.60(s, 447 3H), 4.05(m, 1H), 4.21-4.58(m, 3H), 5.08(m, 1H), 6.70(s, 1H), 6.86(d, 1H, J=8.2Hz), 7.14(m, 1H), 7.32(m, 1H), 7.59(m, 1H), 7.80(d, J=6.0Hz, 2H), 8.71(d, J=6.0Hz, 2H). B090 (DMSO-d₆): 2.82(dd, J=10.2, 12.8Hz, 1H), 3.19-3.26(m, 1H), 397 3.49(s, 3H), 3.67-3.71(m, 1H), 3.83(s, 3H), 3.81-3.94(m, 2H), 4.09-4.12(m, 1H), 4.98-5.01(m, 1H), 7.05-7.23(m, 4H), 8.51(d, J=5.4Hz, 2H), 8.96(d, J=6.4Hz, 2H). B091 (DMSO-d₆): 2.81(m, 1H), 3.20(m, 1H), 3.47(s, 3H), 397 3.56-3.91(m, 2H), 3.83(s, 3H), 4.08(m, 1H), 4.95(d, J=9.3Hz, 1H), 6.78-6.98(m, 2H), 7.09(s, 1H), 7.43(m, 1H), 8.49(d, J=5.4Hz, 2H), 8.94(d, J=5.4Hz, 2H). B092 (DMSO-d₆): 2.94-3.01(1H, m), 3.13-3.20(1H, m), 3.46(3H, s), 417 3.67-3.78(2H, m), 3.88-3.95(1H, m), 4.07-4.10(1H, m), 4.79(1H, d, J=9.8Hz), 6.86(1H, s), 7.47(1H, d, J=8.3Hz), 7.65-7.72(2H, m), 7.98(2H, d, J=5.7Hz), 8.68(2H, d, J=5.5Hz) B093 (DMSO-d₆): 2.78(1H, dd, J=10.3, 12.7Hz), 3.16-3.24(1H, m), 409 3.46(3H, s), 3.62-3.66(1H, m), 3.71(3H, s), 3.78(3H, s), 3.83-4.11(2H, m), 4.97(1H, d, J=9.0Hz), 6.84(1H, s), 6.85-6.88(1H, m), 6.95-7.00(2H, m), 7.99(2H, d, J=5.6Hz), 8.69(2H, d, J=5.9Hz) B094 (DMSO-d₆): 2.78-2.86(m, 1H), 3.17-3.25(m, 1H), 3.49(s, 3H), 408 3.66-3.93(m, 3H), 3.72(s, 3H), 3.78(s, 3H), 4.09-4.13(m, 1H), 4.96-4.99(m, 1H), 6.85-7.09(m, 4H), 8.48(d, J=5.4Hz, 2H), 8.94(d, J=6.0Hz, 2H). B096 (CDCl₃): 3.07(t, J=10.6Hz, 1H), 3.29(td, J=10.3, 3.2Hz, 385 1H), 3.53(d, J=12.2Hz, 1H), 3.58(s, 3H), 3.68(dt, J=13.1, 1.1Hz, 1H), 3.96(td, J=11.9, 2.3Hz, 1H), 4.19(dd, J=13.9, 2.3Hz, 1H), 4.75(dd, J=10.4, 1.1Hz, 2H), 6.72(s, 1H), 6.80(tt, J=8.9, 2.3Hz, 1H), 6.96(dd, J=6.0, 2.3Hz, 2H), 7.79(dd, J=4.6, 1.6Hz, 2H), 8.73(dd, J=4.5, 1.6Hz, 2H). B097 (CDCl₃): 2.78(dd, J=12.8, 10.4Hz, 1H), 3.32(td, J=12.2, 419 3.2Hz, 1H), 3.54(d, J=12.5Hz, 1H), 3.62(s, 3H), 3.82(dt, J=12.9, 1.9Hz, 1H), 4.02(td, J=11.8, 2.3Hz, 1H), 4.23(dd, J=11.6, 2.2Hz, 1H), 5.02(dd, J=10.3, 1.9Hz, 2H), 6.71(s, 1H), 7.24(dd, J=6.9, 2.8Hz, 1H), 7.50(dd, J=11.2, 8.4Hz, 1H), 7.80(dd, J=4.6, 1.5Hz, 2H), 8.70(dd, J=4.5, 1.5Hz, 2H). B098 (CDCl₃): 2.78(dd, J=12.8, 10.4Hz, 1H), 3.32(td, J=12.2, 418 3.2Hz, 1H), 3.54(d, J=12.5Hz, 1H), 3.62(s, 3H), 3.82(dt, J=12.9, 1.9Hz, 1H), 4.02(td, J=11.8, 2.3Hz, 1H), 4.23(dd, J=11.6, 2.2Hz, 1H), 5.02(dd, J=10.3, 1.9Hz, 2H), 6.71(s, 1H), 7.24(dd, J=6.9, 2.8Hz, 1H), 7.50(dd, J=11.2, 8.4Hz, 1H), 7.80(dd, J=4.6, 1.5Hz, 2H), 8.70(dd, J=4.5, 1.5Hz, 2H). B100 (DMSO-d₆): 2.90(dd, J=10.5Hz, 12.9Hz, 1H), 3.23(m, 1H), 446 3.51(s, 3H), 3.70(d, J=13.2Hz, 1H), 3.85(d, J=12.9Hz, 1H), 3.95(m, 1H), 4, 12(d, J=9.6Hz, 1H), 4.96(d, J=8.7Hz, 1H), 7.11(s, 1H), 7.37(m, 1H), 7.60-7.70(m, 2H), 8.50(d, J=6.3Hz, 2H), 8.95(d, J=6.6Hz, 2H). B101 (DMSO-d₆): 3.07(dd, J=12.8, 10.6, 1H), 3.24(m, 1H), 3.47(s, 384 3H), 3.67-4.09(m, 4H), 5.01(d, J=9.4Hz, 1H), 7.06(s, 1H), 7.17(m, 1H), 7.32(m, 1H), 7.61(m, 1H), 8.41(d, J=6.3Hz, 2H), 8.90(d, J=6.3Hz, 2H). B102 (DMSO-d₆): 3.22(t, J=14.4Hz, 1H), 3.58(d, J=19.5Hz, 1H), 408 3.77(s, 3H), 3.26-4.04(m, 4H), 5.29(d, J=9.0Hz, 1H), 6.67(d, J=8.4Hz, 2H), 7.02(s, 1H), 7.27(t, J=8.4Hz, 1H), 8.44(d, J=5.7Hz, 2H), 8.92(d, J=5.7Hz, 2H). B103 d(DMSO-d₆): 3.22(1H, t, J=14.4Hz), 3.58(1H, d, J=19.5Hz), 409 3.77(3H, s), 3.26-4.04(4H, m), 5.29(1H, d, J=9.0Hz), 6.67(2H, d, J=8.4Hz), 7.02(1H, s), 7.27(1H, t, J=8.4Hz), 8.44(2H, d, J=5.7Hz), 8.92(2H, d, J=5.7Hz). B104 d(DMSO-d₆): 3.22(1H, t, J=14.4Hz), 3.58(1H, d, J=19.5Hz), 409 3.77(3H, s), 3.26-4.04(4H, m), 5.29(1H, d, J=9.0Hz), 6.67(2H, d, J=8.4Hz), 7.02(1H, s), 7.27(1H, t, J=8.4Hz), 8.44(2H, d, J=5.7Hz), 8.92(2H, d, J=5.7Hz). B105 (DMSO-d₆): 3.44-3.63(m, 2H), 3.58(s, 3H), 3.81(m, 1H), 3.98(m, 416 1H), 4.21(m, 1H), 5.55(dd, J=2.7Hz, 11.1Hz, 1H), 6.69(s, 1H), 7.20(t, J=7.5Hz, 1H), 7.35(d, J=7.5Hz, 2H), 7.82(d, J=4.5Hz, 2H), 8.70(d, J=4.5Hz, 2H). B106 (CDCl₃): 3.44-3.55(3H, m), 3.59(3H, s), 3.82(1H, dd, J=12.9, 417 10.8Hz), 3.98(1H, m), 4.20(1H, m), 5.55(1H, dd, J=10.8, 2.7Hz), 6.70(1H, s), 7.18-7.38(3H, m), 7.82(2H, dd, J=4.5, 1.5Hz), 8.71(2H, dd, J=4.5, 1.8Hz). B107 (CDCl₃): 3.44-3.55(3H, m), 3.59(3H, s), 3.82(1H, dd, J=12.9, 417 10.8Hz), 3.98(1H, m), 4.20(1H, m), 5.55(1H, dd, J=10.8, 2.7Hz), 6.70(1H, s), 7.18-7.38(3H, m), 7.82(2H, dd, J=4.5, 1.5Hz), 8.71(2H, dd, J=4.5, 1.8Hz). B108 (DMSO-d₆): 3.03(t, J=12.6Hz, 1H), 3.20(t, J=11.1Hz, 1H), 396 3.48(s, 3H), 3.70-3.78(m, 2H), 3.90(m, 1H), 4.05(m, 1H), 4.73(d, J=10.2Hz), 7.03(m, 1H), 7.06(s, 1H), 7.18-7.25(m, 2H), 8.40(d, J=5.7Hz, 2H), 8.90(d, J=5.7Hz, 2H). B109 (CDCl₃): 3.42-3.52(2H, m), 3.57(3H, s), 3.63-3.66(2H, m), 410 3.67(1H, m), 4.13(1H, m), 5.24(1H, dd, J=9.0, 1.8Hz), 6.70(1H, s), 6.95(2H, m), 7.32(1H, m), 7.82(2H, dd, J=4.5, 1.8Hz), 8.72(2H, dd, J=4.5, 1.8Hz). B110 (CDCl₃): 3.42-3.52(2H, m), 3.57(3H, s), 3.63-3.66(2H, m), 385 3.67(1H, m), 4.13(1H, m), 5.24(1H, dd, J=9.0, 1.8Hz), 6.70(1H, s), 6.95(2H, m), 7.32(1H, m), 7.82(2H, dd, J=4.5, 1.8Hz), 8.72(2H, dd, J=4.5, 1.8Hz). B112 (CDCl₃): 1.74-1.79(m, 4H), 2.50-2.53(m, 4H), 3.13(m, 1H), 432 3.32(m, 1H), 3.51-3.68(m, 2H), 3.64(s, 3H), 3.67(s, 2H), 4.00(m, 1H), 4.18(m, 1H), 4.72(m, 1H), 6.70(s, 1H), 7.33-7.44(m, 4H), 7.80(dd, J=4.8, 1.2Hz, 2H), 8.71(dd, J=4.8, 1.2Hz, 2H). B113 (CDCl₃): 1.80-1.82(4H, m), 2.56-5.58(4H, m), 3.12(1H, dd, 431 J=13.2, 10.8Hz), 3.32(1H, m), 3.54(1H, m), 3.58(3H, s), 3.64(1H, m), 3.68(2H, s), 3.98-4.21(2H, m), 4.73(1H, dd, J=10.5, 2.1Hz), 6.69(1H, s), 7.35-7.42(4H, m), 7.79(2H, d, J=4.5, 1.5Hz), 8.71(2H, d, J=4.5, 1.5Hz). B115 (D₂O): 1.24-1.39(1H, m), 1.46-1.67(3H, m), 1.75-1.80(2H, m), 446 2.78-2.86(2H, m), 3.14-3.34(4H, m), 3.44(3H, s), 3.66-3.72(2H, m), 3.91-4.06(2H, m), 4.16(2H, s), 4.79(1H, d, J=10.4Hz), 6.83(1H, s), 7.35-7.47(4H, m), 8.44(2H, d, J=6.5Hz), 8.72(2H, d, J=6.6Hz) B116 (D₂O): 1.81-1.96(2H, m), 2.00-2.16(2H, m), 3.03-3.15(2H, m), 432 3.19-3.31(2H, m), 3.39-3.47(2H, m), 3.50(3H, s), 3.70-3.78(2H, m), 3.95-4.11(2H, m), 4.31(2H, s), 4.85(2H, d, J=10.3Hz), 6.89(1H, s), 7.41-7.56(4H, m), 8.49(2H, d, J=6.0Hz), 8.77(2H, d, J=6.7Hz) B117 (D₂O): 2.74(6H, s), 3.17-3.34(2H, m), 3.48(3H, s), 3.68-3.76(2H, 406 m), 3.97-4.09(2H, m), 4.23(2H, s), 4.83(1H, d, J=9.9Hz), 6.87(1H, s), 7.39-7.52(4H, m), 8.46(2H, d, J=7.1Hz), 8.75(2H, d, J=6.6Hz) B118 (D₂O): 3.11-3.25(4H, m), 3.31-3.36(2H, m), 3.48(3H, s), 448 3.62-3.76(4H, m), 3.98-4.06(4H, m), 4.30(2H, s), 4.83(1H, d, J=8.9Hz), 6.87(1H, s), 7.41-7.52(4H, m), 8.47(2H, d, J=6.8Hz), 8.76(2H, d, J=6.6Hz) B119 (CDCl₃): 1.61-1.78(4H, m), 2.34-2.48(4H, m), 3.06(1H, dd, 431 J=10.5, 12.9Hz), 3.24-3.28(1H, m), 3.35-3.45(1H, m), 3.54(3H, s), 3.68-3.81(2H, m), 3.98-4.02(1H, m), 4.03-4.20(2H, m), 5.05(1H, dd, J=2.1, 10.2Hz), 6.68(1H, s), 7.25-7.26(2H, m), 7.32-7.36(1H, m), 7.57-7.60(1H, m), 7.81(2H, d, J=6.3Hz), 8.72(2H, d, J=6.0Hz) B120 (CDCl₃): 1.31(3H, d, J=6.0Hz), 1.37(3H, d, J=6.1Hz), 2.76(1H, dd, J=10.1, 407 12.6Hz), 3..3-3.5(1H, m), 3.5-3.7(1H, m), 3.63(3H, s), 3.7-3.8( 1H, m), 4.0-4.2(1H, m), 4.2-4.3(1H, m), 4.6-4.7(1H, m), 5.02(1H, dd, J=2.0, 10.1Hz), 6.68(1H, s), 6.88(1H, d, J=8.3Hz), 6.98(1H, t, J=7.4Hz ), 7.2-7.3(1H, m), 7.52(1H, dd, J=1.6, 7.6Hz), 7.81(1H, dd, J=1.6, 4.5Hz), 8.71(2H, dd, 1.5, 4.5Hz) B122 (CDCl₃): 1.34(6H, d, J=6.0Hz), 3.13(1H, dd, J=10.8, 12.9Hz), 3.2-3.4 407 (1H, m), 3.5-3.7(2H, m), 3.57(3H, s), 3.9-4.0(1H, m), 4.1-4.2(1H, m), 4.5-4.6(1H, m), 4.66(1H, dd, J=2.1, 10.5Hz), 6.69(1H, s), 6.9-7.0(2H, m), 7.3-7.4(2H, m), 7.79(2H, dd, J=1.8, 4.5Hz), 8.71(2H, dd, J=1.8, 4.5Hz). B126 (CDCl₃): 0.3-0.4(2H, m), 0.6-0.7(2H, m), 1.2-1.3(1H, m), 2.79(1H, dd, 419 J=10.2, 12.9Hz), 3..3-3.5(1H, m), 3.6-3.7(1H, m), 3.65(3H, s), 3.7-4.0 (3H, m), 4.0-4.1(1H, m), 4.2-4.3(1H, m), 5.09(1H, dd, J=2.1, 10.2Hz), 6.68(1H, s), 6.84(2H, d, J=8.1Hz), 7.03(2H, t, J=7.5Hz), 7.2-7.3(1H, m), 7.53(1H, dd, J=1.5, 7.5Hz), 7.81(1H, dd, J=1.5, 4.5Hz), 8.71(2H, dd, 1.5, 4.5Hz) B128 (CDCl₃): 0.3-0.4(2H, m), 0.6-0.7(2H, m), 1.2-1.3(1H, m), 3.12(1H, dd, 419 J=10.8, 12.9Hz), 3.2-3.4(1H, m), 3.5-3.7(2H, m), 3.57(3H, s), 3.82( 2H, d, J=6.9Hz), 3.9-4.0(1H, m), 4.1-4.2(1H, m), 4.67(1H, dd, J=2.4, 10.8Hz), 6.69(1H, s), 6.93(2H, d, J=8.7Hz), 7.32(2H, d, J=8.7Hz), 7.79 (2H, dd, J=1.8, 4.8Hz), 8.71(2H, dd, J=1.8, 4.8Hz). B130 (DMSO-d₆): 2.98(1H, dd, J=12.6, 14.4Hz), 3.18-3.24(1H, m), 427 3.22(3H, s), 3.46(3H, s), 3.69(1H, d, J=12.3Hz), 3.81(1H, d, J=12.9Hz), 3.89-3.96(1H, m), 4.10(1H, d, J=10.5Hz), 4.89(1H, d, J=9.0Hz), 6.83(1H, s), 7.67(1H, t, J=7.8Hz), 7.80(1H, d, J=7.5Hz), 7.88(1H, d, J=6.9Hz), 7.96(2H, d, J=5.1Hz), 8.00(1H, s), 8.67(2H, d, J=5.1Hz) B140 (CDCl₃): 2.0-2.1(4H, m), 3.16(1H, dd, J=10.7, 12.8Hz), 3.2-3.4(5H, 418 m), 3.5-3.7(2H, m), 3.56(3H, s), 3.9-4.0(1H, m), 4.1-4.2(1H, m), 4.61 (1H, dd, J=2.1, 10.7Hz), 6.57(2H, d, J=8.4Hz), 6.69(1H, s), 7.26(2H, d, J=8.7Hz), 7.80(2H, dd, J=1.4, 4.6Hz), 8.71(2H, dd, J=1.4, 4.6Hz) B143 (CDCl₃): 3.18(1H, dd, J=12.3, 10.1Hz), 3.35(1H, m), 3.59(1H, 425 m), 3.60(3H, s), 3.72(1H, m), 3.98-4.23(2H, m), 4.79(1H, d, J=10.5), 6.70(1H, s), 7.35-7.65(9H, m), 7.80(2H, d, J=5.7Hz), 8.72(2H, d, J=5.7Hz). B184 (DMSO-d₆): 1.99-2.06(2H, m), 2.82-2.89(4H, m), 2.98(1H, dd, 389 J=10.7, 12.9Hz), 3.11-3.22(1H, m), 3.45(3H, s), 3.65-3.70(2H, m), 3.84-3.92(1H, m), 4.01-4.06(1H, m), 4.79(1H, d, J=8.7Hz), 6.83(1H, s), 7.17-7.23(2H, m), 7.29-7.32(1H, m), 7.96(2H, d, J=6.2Hz), 8.66(2H, d, J=6.0Hz) B185 (DMSO-d₆): 3.07(1H, dd, J=10.9, 12.3Hz), 3.18-3.27(1H, m), 399 3.49(3H, s), 3.70-3.74(1H, m), 3.81-3.86(1H, m), 3.93-4.00(1H, m), 4.11-4.15(1H, m), 4.93(1H, d, J=9.5Hz), 6.86(1H, s), 7.51-7.56(2H, m), 7.59-7.62(1H, m), 7.91-7.99(6H, m), 8.68(2H, d, J=5.0Hz) B186 (CDCl₃): 3.21(1H, dd, J=10.5, 13.2Hz), 3.31-3.41(1H, m), 398 3.54-3.67(1H, m), 3.61(3H, s), 3.74-3.78(1H, m), 4.01-4.10(1H, m), 4.23-4.28(1H, m), 4.92(1H, dd, J=2.1, 10.5Hz), 6.71(1H, s), 7.50-7.54(3H, m), 7.80(2H, d, J=6.0Hz), 7.82-7.91(4H, m), 8.71(2H, d, J=6.0Hz) B187 (DMSO-d₆): 3.18(dd, J=10.5, 12.9Hz, 1H), 3.31-3.38(m, 1H), 399 3.53(s, 3H), 3.75-3.79(m, 1H), 4.00-4.18(m, 3H), 5.52-5.55(m, 1H), 7.03(s, 1H), 7.51-8.30(m, 7H), 8.42(d, J=6.0Hz, 2H), 8.92(d, J=5.4Hz, 2H). B188 (CDCl₃): 3.09-3.33(4H, m), 3.53-3.64(2H, m), 3.57(3H, s), 390 3.95-4.02(1H, m), 4.13-4.20(1H, m), 4.58(2H, d, J=8.7Hz), 4.65(1H, dd, J=2.1, 10.8Hz), 6.70(1H, s), 6.78-6.81(1H, m), 7.13-7.16(1H, m), 7.25-7.30(1H, m), 7.80(2H, d, J=6.0Hz), 8.71(2H, d, J=6.0Hz) B189 (DMSO-d₆): 3.07-3.27(m, 2H), 3.48(s, 3H), 3.77(d, J=13.2Hz, 388 1H), 3.93-4.02(m, 2H), 4.13(d, J=10.2Hz, 1H), 5.03(d, J=8.7Hz, 1H), 7.13(s, 1H), 8.05(m, 1H), 8.55(d, J=6.3Hz, 2H), 8.61(d, J=8.1Hz, 1H), 8.90(d, J=5.4Hz, 2H), 8.97(d, J=5.4Hz, 2H). B190 (DMSO-d₆): 3.09-3.23(m, 2H), 3.47(s, 3H), 3.68(d, J=12.6Hz, 354 1H), 3.87-3.94(m, 2H), 4.03(d, J=11.8Hz, 1H), 5.05(D, J-8.4Hz, 1H), 7.05(m, 1H), 7.08(s, 1H), 7.17(d, J=3.3Hz, 1H), 7.53(d, J=5.1Hz, 1H), 8.44(d, J=6.4Hz, 2H), 8.93(d, J=6.4Hz, 2H). B191 (DMSO-d₆): 3.03-3.22(m, 2H), 3.45(s, 3H), 3.69-4.04(m, 4H), 354 4.80(d, J=10.4Hz, 1H), 7.03(s, 1H), 7.19(m, 1H), 7.52-7.55(m, 2H), 8.39(d, J=5.4Hz, 2H), 8.90(d, J=5.4Hz, 2H). B194 (DMSO-d₆): 3.18(m, 1H), 3.50(s, 3H), 3.73-4.17(m, 5H), 349 5.03(d, J=8.4Hz, 1H), 7.15(s, 1H), 7.65(m, 1H), 7.82(d, J=7.8Hz, 1H), 8.20(t, J=7.8Hz, 1H), 8.57(d, J=6.6Hz, 2H), 8.72(d, J=4.5Hz, 1H), 8.98(d, J=6.6Hz, 2H). B195 (DMSO-d₆): 3.07-3.27(m, 2H), 3.48(s, 3H), 3.77(d, 349 J=13.2Hz, 1H), 3.93-4.02(m, 2H), 4.13(d, J=10.2Hz, 1H), 5.03(d, J=8.7Hz, 1H), 7.13(s, 1H), 8.05(m, 1H), 8.55(d, J=6.3Hz, 2H), 8.61(d, J=8.1Hz, 1H), 8.90(d, J=5.4Hz, 1H), 8.90(d, J=5.4Hz, 1H), 8.97(d, J=6.3Hz, 2H). B200 (DMSO-d₆): 3.30(s, 3H), 3.36(m, 2H), 3.88(m, 2H), 4.01(m, 2H), 425 7.10(s, 1H), 7.22-7.42(m, 10H), 8.46(d, J=6.4Hz, 2H), 8.93(d, J=6.3Hz, 2H). B202 (DMSO-d₆): 1.60-2.00(m, 3H), 2.62-2.76(m, 3H), 3.18-3.29(m, 388 2H), 3.48(s, 3H), 3.68-3.83(m, 3H), 4.10-4.17(m, 1H), 7.03(s, 1H), 7.10-7.24(m, 3H), 7.63-7.66(m, 1H), 8.38(d, J=6.1Hz, 2H), 8.89(d, J=6.0Hz, 2H). B203 (CDCl₃): 2.20-2.40(m, 1H), 2.60-2.70(m, 1H), 2.80-3.00(m, 1H), 374 3.00-3.20(m, 1H), 3.29-3.50(m, 4H), 3.59(s, 3H), 4.03-3.20(m, 2H), 6.70(s, 1H), 7.27-7.36(m, 3H), 7.49-7.51(m, 1H), 7.78(dd, J=1.5, 4.8Hz, 2H), 8.70(dd, J=1.8, 4.5Hz, 2H). B205 (DMSO-d₆): 1.30(s, 3H), 1.44(s, 3H), 2.80-2.95(m, 2H), 3.51(s, 377 3H), 3.63-3.80(m, 2H), 5.07(m, 1H), 7.03(s, 1H), 7.30-7.48(m, 5H), 8.35(br s, 2H), 8.89(br s, 2H). B217 (CDCl₃): 1.39(s, 3H), 1.52(s, 3H), 2.89-3.03(m, 2H), 3.39(m, 407 1H), 3.59(s, 3H), 3.63(m, 1H), 3.82(s, 3H), 5.00(m, 1H), 6.69(s, 1H), 6.93(d, J=8.7Hz, 2H), 7.37(d, J=8.7Hz, 2H), 7.79(d, J =6.0Hz, 2H), 8.71(d, J=6.0Hz, 2H). B219 2.97(1H, dd, J=10.5, 12.9Hz), 3.30-3.39(1H, m), 3.53-3.66(1H, 396 m), 3.60(3H, s), 3.75-3.89(1H, m), 3.82(3H, s), 3.95-4.03(1H, m), 4.18-4.23(1H, m), 5.07(1H, d, J=9.6Hz), 6.71(1H, s), 6.79-6.85(1H, m), 6.97-7.04(1H, m), 7.07-7.10(1H, m), 7.82(2H, d, J=6.0Hz), 8.72(2H, d, J=6.0Hz)(CDCl₃) B220 2.79(1H, dd, J=10.1, 12.7Hz), 3.29-3.38(1H, m), 3.54-3.59(1H, 457 m), 3.61(3H, s), 3.79-3.83(1H, m), 3.84(3H, s), 3.94-3.99(1H, m), 4.19-4.23(1H, m), 5.02(1H, dd, J=2.1, 10.1Hz), 6.69(1H, s), 6.77(1H, d, J=8.8Hz), 7.40(1H, dd, J=2.6, 8.7Hz), 7.66(1H, d, J=2.3Hz), 7.82(2H, d, J=6.1Hz), 8.71(2H, d, J=6.1Hz) (CDCl₃) B221 (DMSO-d₆): 1.40-1.60(m, 1H), 1.80-2.20(m, 2H), 2.60-3.00(m, 402 5H), 3.00-3.20(m, 1H), 3.45(s, 3H), 3.50-3.70(m, 2H), 3.73(d, J=11.4Hz, 1H), 3.81(d, J=12.6Hz, 1H), 3.98(d, J=12.3Hz, 1H), 7.01(s, 1H), 7.02-7.10(m, 4H), 8.38(dm, J=6.6Hz, 2H), 8.88-8.92(m, 2H). B225 (CDCl₃): 3.3-3.5(2H, m), 3.63(3H, s), 3.5-3.7(1H, m), 4.0-4.2(2H, m), 406 4.2-4.3(1H, m), 5.20(1H, dd, J=2.7, 9.8Hz), 6.73(1H, s), 7.4-7.6(2H, m), 7.80(1H, d, J=6.3Hz), 7.94(1H, d, J=7.9Hz), 8.03(1H, d, J=8.0Hz), 8.71(1H, d, J=6.3Hz) B234 (DMSO-d₆); 3.01(m, 1H), 3.17(m, 1H), 3.46(s, 3H), 3.70(m, 2H), 393 3.89(m, 1H), 4.05(d, J=12.0Hz, 1H), 4.65(d, J=8.7Hz, 1H), 6.02(s, 2H), 6.89-6.96(m, 2H), 7.01(s, 2H), 8.34(d, J=6.6Hz, 2H), 8.87(d, J=6.6Hz, 2H). B235 (DMSO-d₆); 2.99(dd, J=10.8Hz, 12.9Hz, 1H), 3.12(m, 1H), 407 3.46(s, 3H), 3.69(d, J=12.9, 2H), 3.87(m, 1H), 4.04(d, J=11.7Hz, 1H), 4.24(s, 4H), 4.62(d, J=9.0Hz, 1H), 6.83-6.94(m, 3H), 7.05(s, 1H), 8.41(d, J=6.6Hz, 2H), 8.91(d, J=6.6Hz, 2H). B236 (DMSO-d₆); 3.04(m, 1H), 3.19(m, 1H), 3.47(s, 3H), 3.69-4.09(m, 409 6H), 3.75(s, 3H), 3.77(s, 3H), 4.67(d, J=9.0Hz, 1H), 6.93-7.05(m, 4H), 8.38(d, J=6.3Hz, 2H), 8.89(d, J=6.3Hz, 2H). B237 (DMSO-d₆): 2.5-2.6(1H, m), 2.9-3.2(6H, m), 3.44(3H, s), 389 3.4-3.8(4H, s), 3.9-4.0(1H, m), 6.99(1H, s), 7.1-7.2(2H, m), 7.2-7.3(2H, m), 7.88(1H, d, J=6.9Hz), 8.31(2H, d, J=6.3Hz), 8.00(1H, s), 8.88(2H, d, J=6.5Hz) B238 (DMSO): 3.05(1H, dd, J=10.8, 12.8Hz), 3.15-3.26(1H, m), 397 3.45(3H, s), 3.65(1H, d, J=13.4Hz), 3.73-3.91(2H, m), 3.79(3H, s), 4.05(1H, d, J=13.6Hz), 4.95(1H, d, J=8.9Hz), 6.82-6.89(3H, m), 7.43-7.49(1H, m), 7.98(2H, d, J=5.9Hz), 8.68(2H, d, J=5.8Hz) B239 (DMSO): 2.88(1H, dd, J=10.2, 13.0Hz), 3.19-3.27(1H, m), 417 3.47(3H, s), 3.66(1H, d, J=13.4Hz), 3.85(1H, d, J=13.4Hz), 3.93(1H, t, J=11.6Hz), 4.11(1H, d, J=9.6Hz), 5.03(1H, d, J=8.5Hz), 6.84(1H, s), 7.50-7.54(1H, m), 7.63-7.67(2H, m), 7.97(2H, d, J=6.0Hz), 8.67(2H, d, J=5.9Hz) B240 (CDCl₃): 3.00(1H, dd, J=12.9, 10.5Hz), 3.21-3.41(3H, m), 391 3.55(1H, m), 3.59(3H, s), 3.83-4.21(3H, m), 4.61(2H, m), 4.95(1H, d, J=8.4Hz), 6.69(1H, s), 6.91(1H, m), 7.16-7.31(2H, m), 7.84(2H, dd, J=4.5, 1.5Hz), 8.71(2H, dd, J=4.5, 1.5Hz). B241 (DMSO-d₆): 2.80(1H, dd, J=10.2, 12.9Hz), 3.1-3.3(1H, m), 3.46(3H, 409 s), 3.6-3.7(1H, m), 3.77(3H, s), 3.82(3H, s), 3.7-3.9(2H, m), 4.0-4.1(1H, m), 4.9-5.0(1H, m), 6.5-6.6(2H, m), 6.82(1H, s), 7.3-7.4(1H, m), 7.79 (2H, dd, J=1.5, 4.5Hz), 8.69(2H, dd, J=1.5, 4.5Hz). B242 (DMSO-d₆): 2.80(1H, dd, J=10.2, 12.9Hz), 3.1-3.3(1H, m), 3.46(3H, 409 s), 3.6-3.7(1H, m), 3.77(3H, s), 3.82(3H, s), 3.7-3.9(2H, m), 4.0-4.1(1H, m), 4.9-5.0(1H, m), 6.5-6.6(2H, m), 6.82(1H, s), 7.3-7.4(1H, m), 7.79 (2H, dd, J=1.5, 4.5Hz), 8.69(2H, dd, J=1.5, 4.5Hz). B243 (DMSO-d₆): 2.7-2.9(1H, m), 3.1-3.3(1H, m), 3.46(3H, s), 3.6-3.7(1H, 488 m), 3.89(3H, s), 3.90(3H, s), 3.7-3.9(2H, m), 4.0-4.1(1H, m), 4.9-5.0 (1H, m), 6.80(1H, s), 6.83(1H, s), 7.51(1H, s), 7.9-8.0(2H, m), 8.6-8.7(2H, m) B244 (DMSO-d₆): 2.80(1H, dd, J=10.2, 12.9Hz), 3.1-3.3(1H, m), 3.46(3H, 409 s), 3.6-3.7(1H, m), 3.77(3H, s), 3.82(3H, s), 3.7-3.9(2H, m), 4.0-4.1(1H, m), 4.9-5.0(1H, m), 6.5-6.6(2H, m), 6.82(1H, s), 7.3-7.4(1H, m), 7.79 (2H, dd, J=1.5, 4.5Hz), 8.69(2H, dd, J=1.5, 4.5Hz). B245 (CDCl₃): 2.80(1H, dd, J=12.6, 10.4Hz), 3.33(1H, m), 3.55(1H, 397 m), 3.62(3H, s), 3.77(1H, m), 3.85(3H, s), 4.01(1H, m), 4.21(1H, m), 5.02(1H, d, J=9.6Hz), 6.61-6.75(3H, m), 7.48(1H, m), 7.82(2H, d, J=5.7Hz), 8.71(2H, d, J=5.7Hz). B246 (CDCl₃): 3.18(1H, dd, J=12.3, 10.1Hz), 3.35(1H, m), 3.59(1H, 425 m), 3.60(3H, s), 3.72(1H, m), 3.98-4.23(2H, m), 4.79(1H, d, J=10.5), 6.71(1H, s), 7.36-7.66(9H, m), 7.80(2H, d, J=5.7Hz), 8.72(2H, d, J=5.7Hz). B247 (CDCl₃): 0.32-0.34(2H, m), 0.62-0.67(2H, m), 1.22(1H, m), 437 2.76(1H, dd, J=12.6, 10.2Hz), 3.37(1H, m), 3.60-4.25(7H, m), 3.65(3H, s), 5.02(1H, d, J=9.3Hz), 6.54-6.72(3H, m), 7.47(1H, dd, J=8.1, 7.2Hz), 7.81(2H, d, J=6.0Hz), 8.71(2H, d, J=6.0Hz). B248 (CDCl₃): 1.33(3H, d, J=6.0Hz), 1.38(3H, d, J=6.0Hz), 2.72(1H, 425 dd, J=12.6, 10.2Hz), 3.35(1H, m), 3.57-3.72(5H, m), 4.03-4.25(2H, m), 4.57(1H, m), 4.95(1H, d, J=8.7Hz), 6.58-6.71(3H, m), 7.46(1H, dd, J=8.4, 7.2Hz), 7.80(2H, d, J=6.0Hz), 8.71(2H, d, J=6.0Hz). B249 (DMSO): 2.98(1H, dd, J=10.5, 13.0Hz), 3.18-3.30(1H, m), 447 3.47(3H, s), 3.66(1H, d, J=12.5Hz), 3.80(1H, d, J=13.0Hz), 3.84(3H, s), 3.92(1H, dd, J=9.5, 11.7Hz), 4.18(1H, d, J=11.7Hz), 5.01(1H, dd, J=2.0, 10.4Hz), 6.84(1H, s), 7.50(1H, d, J=2.6Hz), 7.67(1H, d, J=2.7Hz), 7.99(2H, d, J=6.2Hz), 8.69(2H, d, J=6.1Hz) B250 (DMSO): 3.01(1H, dd, J=10.8, 12.9Hz), 3.14-3.18(1H, m), 441 3.46(3H, s), 3.66-3.76(2H, m), 3.86-3.93(1H, m), 4.06(1H, d, J=11.7Hz), 4.74(1H, d, J=8.7Hz), 6.84(1H, s), 6.98-7.04(4H, m), 7.11-7.18(1H, m), 7.37-7.48(4H, m), 7.97(2H, d, J=6.3Hz), 8.69(2H, d, J=6.0Hz) B251 (CDCl₃): 3.06(1H, dd, J=12.9, 10.5Hz), 3.42(1H, m), 3.60(1H, 391 m), 3.67(3H, s), 4.07-4.32(3H, m), 5.38(1H, d, J=10.2Hz), 6.73(1H, s), 7.45-7.61(2H, m), 7.82(1H, d, J=9.0Hz), 7.89(2H, d, J=6.0Hz), 8.72(2H, d, J=6.0Hz). B252 (CDCl₃): 3.3-3.7(4H, m), 3.58(3H, s), 3.96(1H, t, J=11.7Hz), 4.17(1H, 401 dd, J=4.5, 8.3Hz), 6.70(1H, s), 7.0-7.1(1H, m), 7.2-7.4(2H, m), 7.82 (2H, d, J=5.7Hz), 8.71(2H, d, J=5.6Hz) B253 (CDCl₃): 2.81(1H, dd, J=10.5, 12.8Hz), 3.3-3.4(1H, m), 3.5-3.7(2H, 401 m), 3.63(3H, s), 3.7-3.9(1H, m), 4.03(1H, dt, J=2.2, 11.6Hz), 4.2-4.3(1H, m), 5.0-5.1(1H, m), 6.71(1H, s), 7.0-7.2(2H, m), 7.63(1H, dd, J=6.3, 8.7Hz), 7.80(2H, d, J=6.0Hz), 8.71(2H, d, J=5.6Hz). B254 (DMSO): 2.89(1H, dd, J=10.2, 12.8Hz), 3.19-3.30(1H, m), 455 3.49(3H, s), 3.67(1H, d, J=13.0Hz), 3.86-3.95(2H, m), 3.89(3H, s), 4.13(1H, d, J=9.8Hz), 5.07(1H, d, J=8.4Hz), 6.84(1H, s), 7.15(1H, d, J=8.6Hz), 7.29-7.37(1H, m), 7.42-7.48(2H, m), 7.60-7.63(3H, m), 7.72(1H, d, J=2.3Hz), 8.00(2H, d, J=6.1Hz), 8.69(2H, d, J=6.0Hz) B255 (DMSO): 2.85(1H, dd, J=10.2, 12.9Hz), 3.19-3.28(1H, m), 473 3.49(3H, s), 3.67(1H, d, J=12.3Hz), 3.85-3.95(2H, m), 3.88(3H, s), 4.13(1H, d, J=9.7Hz), 5.06(1H, d, J=8.3Hz), 6.84(1H, s), 7.14(1H, d, J=8.6Hz), 7.21-7.30(2H, m), 7.57-7.70(4H, m), 8.00(2H, d, J=6.1Hz), 8.69(2H, d, J=6.1Hz) B256 (DMSO): 2.93(1H, dd, J=10.3, 13.0Hz), 3.19-3.31(1H, m), 456 3.49(3H, s), 3.68(1H, d, J=12.6Hz), 3.86-3.95(2H, m), 3.90(3H, s9), 4.13(1H, d, J=9.5Hz), 5.08(1H, d, J=8.3Hz), 6.84(1H, s), 7.20(1H, d, J=8.6Hz), 7.41-7.50(1H, m), 7.66-7.70(1H, m), 7.76(1H, d, J=2.4Hz), 8.00(2H, d, J=6.2Hz), 8.00-8.04(1H, m), 8.50-8.54(1H, m), 8.69(2H, d, J=6.1Hz), 8.85(1H, d, J=2.0Hz) B257 (DMSO): 2.99(1H, dd, J=10.8, 12.9Hz), 3.10-3.21(1H, m), 385 3.46(3H, s), 3.66-3.77(2H, m), 3.87-3.95(1H, m), 4.08(1H, d, J=11.7Hz), 4.76(1H, d, J=8.4Hz), 6.85(1H, s), 7.28-7.33(1H, m), 7.41-7.56(2H, m), 7.96(2H, d, J=6.0Hz), 8.69(2H, d, J=6.0Hz) B258 (DMSO): 2.99(1H, dd, J=10.7, 12.6Hz), 3.13-3.22(1H, m), 445 3.46(3H, s), 3.67-3.77(2H, m), 3.87-3.95(1H, m), 4.08(1H, d, J=11.5Hz), 4.76(1H, d, J=9.2Hz), 6.86(1H, s), 7.41(1H, t, J=8.6Hz), 7.48-7.54(1H, m), 7.72-7.81(1H, m), 7.98(2H, d, J=5.9Hz), 8.69(2H, d, J=5.9Hz) B259 (DMSO-d₆): 1.23(6H, d, J=5.9Hz), 2.7-2.9(1H, m), 3.1-3.3(1H, m), 3.47 437 (3H, s), 3.6-3.7(1H, m), 3.7-4.0(2H, m), 3.78(3H, s), 4.0-4.1(1H, m), 4.4-4.6(1H, m), 4.9-5.0(1H, m), 6.8-7.0(4H, m), 8.00(2H, d, J=5.3Hz), 8.69(2H, d, J=5.6Hz) B260 (DMSO-d₆): 2.17(3H, s), 2.22(3H, s), 2.7-2.8(1H, m), 3.1-3.2(1H, m), 407 3.46(3H, s), 3.6-3.7(1H, m), 3.7-3.9(2H, m), 3.79(3H, s), 4.0-4.1(1H, m), 6.84(2H, s), 7.19(1H, s), 7.99(2H, d, J=5.0Hz), 8.69(2H, d, J=4.7Hz) B261 (DMSO-d₆): 1.27(6H, d, J=5.1Hz), 2.7-2.9(1H, m), 3.1-3.3(1H, m), 3.46 437 (3H, s), 3.6-4.0(3H, m), 3.84(3H, s), 4.0-4.1(1H, m), 4.6-4.7(1H, m), 4.9-5.0(1H, m), 6.5-6.6(2H, m), 6.84(1H, s), 7.2-7.3(1H, m), 7.99(2H, d, J=6.0Hz), 8.69(2H, d, J=6.0Hz) B262 (DMSO-d₆): 2.7-2.9(1H, m), 3.2-3.3(1H, m), 3.47(3H, s), 3.6-3.7(1H, 404 m), 3.8-4.0(5H, m), 4.1-4.2(1H, m), 5.0-5.1(1H, m), 6.86(1H, s), 7.26(1H, d, J=8.5Hz), 7.78(1H, s), 7.84(1H, d, J=8.5Hz), 8.00(2H, d, J=5.7Hz), 8.70(2H, d, J=5.6Hz) B263 (CDCl₃): 1.40(3H, t, J=6.9Hz), 3.38-3.47(3H, m), 3.86(6H, s), 423 3.91-4.17(5H, m), 5.44(1H, dd, J=10.8, 2.1Hz), 6.60(1H, d, J=8.4Hz), 6.67(1H, s), 7.24-7.30(2H, m), 7.84(2H, d, J=6.0Hz), 8.70(2H, d, J=6.0Hz). B264 (CDCl₃): 0.95(3H, t, J=7.2Hz), 1.77-1.86(2H, m), 3.34-3.47(2H, 437 m), 3.89(6H, s), 3.92-4.48(5H, m), 5.44(1H, d, J=8.4Hz), 6.60(1H, d, J=8.4Hz), 6.67(1H, s), 7.24-7.30(2H, m), 7.84(2H, d, J=6.0Hz), 8.70(2H, d, J=6.0Hz). B265 (DMSO-d₆): 1.30(3H, t, J=6.6Hz), 2.97-4.10(8H, m), 4.78(1H, d, 381 J=9.6Hz), 7.08(1H, s), 7.19-7.25(2H, m), 7.48-7.54(2H, m), 8.35(2H, d, J=6.0Hz), 8.88(2H, d, J=6.0Hz). B266 (DMSO-d₆): 0.88(3H, t, J=7.2Hz), 1.69-1.77(2H, m), 1.26(1H, 395 m), 3.00-3.26(2H, m), 3.59(2H, m), 3.88-4.12(3H, m), 4.78(1H, d, J=9.6Hz), 7.08(1H, s), 7.20-7.26(2H, m), 7.49-7.54(2H, m), 8.36(2H, d, J=6.0Hz), 8.90(2H, d, J=6.0Hz). B267 (CDCl₃): 0.39-0.43(2H, m), 0.53-0.58(2H, m), 1.26(1H, m), 407 3.09(1H, dd, J=12.6, 10.8Hz), 3.29-3.51(3H, m), 3.92(1H, m), 3.61(3H, s), 3.77(1H, m), 3.85(3H, s), 3.99(1H, m), 4.21(1H, m), 5.01(1H, dd, J=9.9, 1.8Hz), 6.63(1H, dd, J=10.8, 2.4Hz), 6.69(1H, s), 6.72(1H, m), 7.48(1H, dd, J=8.4, 6.9Hz), 7.82(2H, dd, J=4.8, 1.8Hz), 8.71(2H, dd, J=4.8, 1.8Hz). B268 (CDCl₃): 3.3-3.4(1H, m), 3.5-3.6(2H, m), 3.59(3H, s), 3.83(3H, s), 3.9-4.1 420 (2H, m), 4.1-4.2(1H, m), 4.96(1H, dd, J=2.4, 10.2Hz), 6.50(1H, s), 6.73(1H, s), 6.9-7.1(1H, m), 7.2-7.3(2H, m), 7.81(2H, dd, J=1.5, 4.5Hz), 8.74(2H, dd, J=1.2, 4.5Hz) B269 (DMSO-d₆): 2.78(1H, dd, J=10.2, 12.8Hz), 3.1-3.3(1H, m), 3.47(3H, 413 s), 3.6-3.7(1H, m), 3.8-4.0(5H, m), 4.0-4.1(1H, m), 4.9-5.0(1H, m), 6.84 (1H, s), 7.06(1H, dd, J=2.0, 8.2Hz), 7.13(1H, d, J=2.0Hz), 7.44(1H, d, J=8.2Hz), 7.99(2H, dd, J=1.6, 4.7Hz), 8.69(2H, dd, J=1.6, 4.7Hz) B270 (DMSO-d₆): 3.1-3.3(1H, m), 3.42(3H, s), 3.5-3.6(1H, m), 3.6-3.7(2H, 415 m), 3.7-3.9(1H, m), 3.86(3H, s), 3.9-4.0(1H, m), 5.1-5.2(1H, m), 6.8-7.0 (3H, m), 7.9-8.0(2H, m), 8.6-8.7(2H, m) B271 (CDCl₃): 3.3-3.51H, m), 3.5-3.7(2H, m), 3.61(3H, s), 3.9-4.3(3H, m), 390 5.35(1H, dd, J=2.8, 9.8Hz), 6.73(1H, s), 7.3-7.4(1H, m), 7.6-7.7(2H, m), 7.80(2H, dd, J=1.5, 4.7Hz), 7.96(1H, d, J=8.1Hz), 8.71(2H, dd, J=1.5, 4.7Hz) B272 (DMSO-d₆): 2.7-2.8(1H, m), 3.2-3.3(1H, m), 3.47(3H, s), 3.6-3.7(1H, 404 m), 3.8-4.0(5H, m), 4.1-4.2(1H, m), 5.0-5.1(1H, m), 6.84(1H, s), 7.48(1H, d, J=8.1Hz), 7.54(1H, s), 7.62(1H, d, J=8.1Hz), 7.99(2H, dd, J=1.2, 4.5Hz), 8.70(2H, d, J=1.2, 4.5Hz) B273 (DMSO-d₆): 2.8-2.9(1H, m), 3.1-3.3(1H, m), 3.49(3H, s), 3.6-3.8(1H, 455 m), 3.8-4.0(5H, m), 4.1-4.2(1H, m), 5.0-5.1(1H, m), 6.86(1H, s), 7.2-7.6 (5H, m), 7.72(2H, d, J=7.5Hz), 8.01(2H, d, J=6.3Hz), 8.70(2H, d, J=6.0Hz) B274 (CDCl₃): 1.9-2.1(4H, m), 2.83(1H, dd, J=10.2, 12.6Hz), 3.2-3.5(5H, 448 m), 3.5-3.7(1H, m), 3.62(3H, s), 3.79(3H, s), 3.8-3.9(1H, m), 3.9-4.1(1H, m), 4.2-4.3(1H, m), 5.0-5.1(1H, m), 6.49(1H, dd, J=3.0, 9.0Hz), 6.68 (1H, s), 6.8-6.9(2H, m), 7.82(2H, d, J=6.0Hz), 8.71(2H, d, J=6.0Hz) B275 (CDCl₃): 1.9-2.1(4H, m), 2.89(1H, dd, J=10.3, 12.8Hz), 3.2-3.4(5H, 448 m), 3.5-3.6(1H, m), 3.60(3H, s), 3.75(3H, s), 3.7-3.8(1H, m), 3.9-4.1(1H, m), 4.1-4.3(1H, m), 4.99(1H, dd, J=2.1, 10.2Hz), 6.08(1H, d, J=2.1Hz), 6.21(1H, dd, J=2.0, 8.5Hz), 6.68(1H, s), 7.31(1H, d, J=8.5Hz), 7.82 (2H, dd, J=1.6, 4.6Hz), 8.71(2H, dd, J=1.6, 4.6Hz) B276 (DMSO): 2.84(1H, dd, J=10.5, 12.8Hz), 3.19-3.26(1H, m), 473 3.49(3H, s), 3.66(1H, d, J=12.7Hz), 3.88-3.94(2H, m), 3.90(3H, s), 4.12(1H, d, J=10.3Hz), 5.06(1H, d, J=9.2Hz), 6.85(1H, s), 7.17(1H, d, J=8.6Hz), 7.26-7.33(2H, m), 7.36-7.40(1H, m), 7.48-7.53(2H, m), 7.63(1H, s), 8.01(2H, d, J=5.7Hz), 8.69(2H, d, J=5.6Hz) B277 (DMSO): 2.90(1H, dd, J=10.3, 12.8Hz), 3.26-3.29(1H, m), 485 3.49(3H, s), 3.67(1H, d, J=13.1Hz), 3.82(3H, s), 3.85-3.94(2H, m), 3.89(3H, s), 4.14(1H, d, J=9.6Hz), 5.06(1H, d, J=8.7Hz), 6.85(1H, s), 6.90-6.93(1H, m), 7.12-7.19(3H, m), 7.34-7.39(1H, m), 7.60-7.64(1H, m), 7.71(1H, d, J=2.1Hz), 8.01(2H, d, J=6.0Hz), 8.69(2H, d, J=5.9Hz) B278 (DMSO): 2.84(1H, dd, J=10.5, 12.6Hz), 3.18-3.25(1H, m), 523 3.48(3H, s), 3.66(1H, d, J=13.2Hz), 3.86-3.93(2H, m), 3.90(3H, s), 4.10(1H, d, J=10.2Hz), 5.07(1H, d, J=9.0Hz), 6.85(1H, s), 7.16(1H, d, J=8.7Hz), 7.39-7.45(2H, m), 7.50-7.52(2H, m), 7.72(1H, d, J=1.8Hz), 8.01(2H, d, J=5.4Hz), 8.70(2H, d, J=5.4Hz) B279 (DMSO): 1.52-1.71(4H, m), 2.32-2.43(4H, m), 2.76(1H, dd, 462 J=10.2, 12.9Hz), 3.18-3.25(1H, m), 3.47(3H, s), 3.54(2H, d, J=3.9Hz), 3.65(1H, d, J=12.9Hz), 3.81-3.91(2H, m), 3.82(3H, s), 4.10(1H, d, J=9.9Hz), 4.99(1H, d, J=8.7Hz), 6.84(1H, s), 6.97(1H, d, J=8.4Hz), 7.17-7.23(1H, m), 7.39(1H, d, J=1.8Hz), 8.00(2H, d, J=6.0Hz), 8.69(2H, d, J=6.0Hz) B280 (DMSO): 3.11(1H, dd, J=10.3, 12.6Hz), 3.41-3.48(1H, m), 473 3.67(3H, s), 3.86(1H, d, J=12.7Hz), 4.03-4.13(2H, m), 4.08(3H, s), 4.32(1H, d, J=11.0Hz), 5.25(1H, d, J=8.6Hz), 7.04(1H, s), 7.33-7.36(2H, m), 7.60-7.70(3H, m), 7.86(1H, dd, J=2.4, 8.5Hz), 7.93(1H, d, J=2.3Hz), 8.19(2H, d, J=6.1Hz), 8.88(2H, d, J=6.0Hz) B281 (DMSO): 2.83(1H, dd, J=10.2, 12.9Hz), 3.14-3.25(1H, m), 485 3.49(3H, s), 3.66(1H, d, J=12.6Hz), 3.76(3H, s), 3.84-3.93(2H, m), 3.87(3H, s), 4.10(1H, d, J=11.4Hz), 5.04(1H, d, J=8.7Hz), 6.85(1H, s), 6.98-7.03(1H, m), 7.07-7.11(2H, m), 7.25-7.34(2H, m), 7.41-7.47(1H, m), 7.53(1H, d, J=2.4Hz), 8.01(2H, d, J=6.3Hz), 8.70(2H, d, J=6.0Hz) B282 (DMSO): 2.88(1H, dd, J=10.3, 12.9Hz), 3.18-3.28(1H, m), 485 3.48(3H, s), 3.67(1H, d, J=12.8Hz), 3.79(3H, s), 3.85-3.94(2H, m), 3.87(3H, s), 4.13(1H, d, J=11.6Hz), 5.05(1H, d, J=8.4Hz), 6.85(1H, s), 7.01(1H, d, J=8.8Hz), 7.11(1H, d, J=8.7Hz), 7.53-7.56(3H, m), 7.66(1H, d, J=2.3Hz), 8.00(2H, d, J=6.1Hz), 8.69(2H, d, J=6.0Hz) B283 (DMSO): 2.77(1H, dd, J=10.2, 12.8Hz), 3.10-3.21(1H, m), 470 3.47(3H, s), 3.65(1H, d, J=12.9Hz), 3.80(3H, s), 3.84-3.92(2H, m), 4.04-4.10(1H, m), 4.98(1H, d, J=8.4Hz), 6.68-6.73(1H, m), 6.85(1H, s), 6.92-6.98(3H, m), 7.01-7.08(1H, m), 7.14-7.20(2H, m), 7.23(1H, d, J=2.6Hz), 7.94(1H, s), 8.01(2H, d, J=6.1Hz), 8.69(2H, d, J=6.1Hz) B284 (CDCl₃): 3.37-3.54(3H, m), 3.59(3H, s), 3.88(1H, m), 4.03(1H, 389 m), 4.18(1H, m), 4.99(1H, dd, J=10.2, 2.4Hz), 6.73(1H, s), 6.78(1H, s), 7.25-7.33(2H, m), 7.49-7.58(2H, m), 7.81(2H, dd, J=4.5, 1.8Hz), 8.72(dd, J=4.5, 1.8Hz). B285 (CDCl₃): 2.80(1H, dd, J=12.9, 10.2Hz), 3.35(1H, m), 3.55(1H, 397 m), 3.61(3H, s), 3.77(1H, m), 3.85(3H, s), 3.99(1H, m), 4.21(1H, m), 5.01(1H, dd, J=9.9, 1.8Hz), 6.63(1H, dd, J=10.8, 2.4Hz), 6.69(1H, s), 6.72(1H, m), 7.48(1H, dd, J=8.4, 6.9Hz), 7.82(2H, dd, J=4.8, 1.8Hz), 8.71(2H, dd, J=4.8, 1.8Hz). B286 (CDCl₃): 3.33-3.53(3H, m), 3.58(3H, s), 3.88(1H, m), 3.98(1H, 419 m), 4.01(3H, s), 4.18(1H, m), 5.00(1H, m), 6.72(1H, s), 6.77(1H, s), 6.82(1H, m), 7.16-7.19(2H, m), 7.83(2H, d, J=6.0Hz), 8.72(2H, d, J=6.0Hz). B287 (DMSO-d₆): 1.9-2.1(4H, m), 2.9-3.2(3H, m), 3.2-3.5(3H, m), 3.51(3H, 538 s), 3.72(1H, d, J=11.7Hz), 3.90(3H, s), 3.8-4.1(2H, m), 4.14(1H, d, J=12.9Hz), 4.41(2H, d, J=5.4Hz), 5.08(1H, d, J=9.6Hz), 7.08(1H, s), 7.18 (1H, d, J=8.7Hz), 7.4-7.6(1H, m), 7.6-7.8(2H, m), 7.79(1H, s), 7.96(1H, s), 8.46(2H, d, J=6.0Hz), 8.93(2H, d, J=5.4Hz), 11.5(1H, brd) B288 (CDCl₃): 1.9-2.1(4H, m), 3.17(1H, dd, J=10.5, 12.9Hz), 3.3-3.4(5H, 418 m), 3.5-3.6(1H, m), 3.57(3H, s), 3.7-3.8(1H, m), 3.9-4.1(1H, m), 4.1-4.2 (1H, m), 4.69(1H, dd, J=2.1, 10.5Hz), 6.73(1H, s), 6.54(1H, m), 6.60(1H, d, J=1.2Hz), 6.6-6.7(2H, m), 7.2-7.3(1H, m)7.81(2H, dd, J=1.5, 4.5Hz), 8.71(2H, dd, J=1.8, 4.5Hz) B289 (CDCl₃): 1.9-2.1(4H, m), 3.17(1H, dd, J=10.5, 12.9Hz), 3.3-3.4(5H, 418 m), 3.5-3.6(1H, m), 3.57(3H, s), 3.7-3.8(1H, m), 3.9-4.1(1H, m), 4.1-4.2 (1H, m), 4.69(1H, dd, J=2.1, 10.5Hz), 6.73(1H, s), 6.54(1H, m), 6.60(1H, d, J=1.2Hz), 6.6-6.7(2H, m), 7.2-7.3(1H, m)7.81(2H, dd, J=1.5, 4.5Hz), 8.71(2H, dd, J=1.8, 4.5Hz) B290 (CDCl₃): 2.87(1H, m), 3.38(1H, m), 3.58(1H, m), 3.64(3H, s), 473 3.84(1H, m), 3.91(3H, s), 4.03(1H, m), 4.22(1H, m), 5.11(1H, m), 6.70(1H, s), 7.08-7.46(6H, m), 7.60(1H, d, J=5.1Hz), 7.83(2H, d, J=6.0Hz), 8.72(2H, d, J=6.0Hz). B291 (CDCl₃): 2.86(1H, dd, J=12.9, 10.2Hz), 3.38(1H, m), 3.57(1H, 473 m), 3.64(3H, s), 3.88(1H, m), 3.93(3H, s), 4.02(1H, m), 4.26(1H, m), 5.10(1H, m), 6.70(1H, s), 7.05-7.07(2H, m), 7.21-7.42(4H, m), 7.60(1H, d, J=4.8Hz), 7.83(2H, dd, J=4.5, 1.2Hz), 8.72(2H, dd, J=4.5, 1.2Hz). B292 (CDCl₃): 2.86(1H, dd, J=12.9, 10.2Hz), 3.35(1H, m), 3.57(1H, 473 m), 3.64(3H, s), 3.88(1H, m), 3.93(3H, s), 4.02(1H, m), 4.22(1H, m), 5.10(1H, m), 6.70(1H, s), 7.04(1H, s), 7.10-7.23(3H, m), 7.52-7.60(3H, m), 7.83(2H, d, J=6.0Hz), 8.72(2H, d, J=6.0Hz). B293 (DMSO): 2.86(1H, dd, J=10.2, 12.8Hz), 3.22-3.30(1H, m), 456 3.49(3H, S), 3.68(1H, d, J=12.1Hz), 3.87-3.96(2H, m), 3.91(3H, s), 4.16(1H, d, J=11.9Hz), 5.07(1H, d, J=8.7Hz), 6.85(1H, s), 7.16(1H, d, J=8.7Hz), 7.27-7.32(1H, m), 7.81-7.94(2H, m), 7.99-8.05(3H, m), 8.26(1H, d, J=2.3Hz), 8.63-8.65(1H, m), 8.69(2H, d, J=6.0Hz) B294 (DMSO): 2.90(1H, dd, J=10.5, 12.9Hz), 3.20-3.29(1H, m), 486 3.49(3H, s), 3.68(1H, d, J=12.3Hz), 3.84-3.92(2H, m), 3.91(3H, s), 3.95(3H, s), 4.15(1H, d, J=12.0Hz), 5.07(1H, d, J=9.0Hz), 6.73(1H, d, J=8.1Hz), 6.85(1H, s), 7.17(1H, d, J=8.7Hz), 7.48(1H, d, J=7.5Hz), 7.76(1H, t, J=7.8Hz), 8.01(2H, d, J=6.0Hz), 8.07(1H, dd, J=2.1, 8.7Hz), 8.15(1H, d, J=2.1Hz), 8.69(1H, d, J=6.0Hz) B295 (DMSO): 2.91(1H, dd, J=10.2, 12.8Hz), 3.21-3.28(1H, m), 486 3.48(3H, s), 3.67(1H, d, J=12.5Hz), 3.84-3.94(2H, m), 3.88(3H, s), 3.89(3H, s), 4.12(1H, d, J=9.9Hz), 5.06(1H, d, J=8.5Hz), 6.85(1H, s), 6.90(1H, d, J=8.7Hz), 7.15(1H, d, J=8.6Hz), 7.58-7.63(1H, m), 7.67(1H, d, J=2.4Hz,), 7.94-7.98(1H, m), 8.01(2H, d, J=6.1Hz), 8.42(1H, d, J=2.3Hz), 8.69(2H, d, J=6.2Hz) B296 (DMSO): 2.84(1H, dd, J=10.5, 12.6Hz), 3.18-3.25(1H, m), 487 3.48(3H, s), 3.62(1H, d, J=13.2Hz), 3.85-3.99(2H, m), 3.87(3H, s), 3.94(6H, s), 4.11(1H, d, J=10.2Hz), 5.04(1H, d, J=9.6Hz), 6.85(1H, s), 7.12(1H, d, J=8.7Hz), 7.46(1H, d, J=8.4Hz), 7.56(1H, s), 8.00(2H, d, J=4.8Hz), 8.32(1H, s), 8.70(2H, d, J=5.1Hz) B297 (CDCl₃): 2.2-2.4(1H, m), 2.4-2.6(1H, m), 3.3-3.4(1H, m), 3.5-3.8(3H, 391 m), 3.58(3H, s), 3.9-4.1(1H, m), 4.1-4.3(2H, m), 4.5-4.6(1H, m), 6.71(1H, s), 6.87(1H, d, J=8.4Hz), 7.00(1H, t, J=7.8Hz), 7.25(1H, t, J=8.4Hz), 7.62(1H, dd, J=1.5, 8.1Hz), 7.78(2H, dd, J=1.5, 4.5Hz), 8.71(2H, dd, J=1.8, 6.6Hz) B298 (CDCl₃): 1.8-2.0(3H, m), 2.3-2.4(1H, m), 3.2-3.4(1H, m), 3.44(3H, s) 405 3.5-3.6(1H, m), 3.7-3.9(3H, m), 4.1-4.2(1H, m), 4.2-4.4(2H, m), 6.66(1H, s), 7.02(1H, dd, J=1.2, 8.1Hz), 7.14(1H, t, J=7.2Hz), 7.22(1H, dd, J=1.8, 7.5Hz), 7.59(1H, dd, J=1.8, 7.8Hz), 7.79(2H, dd, J=1.5, 4.5Hz), 8.71(2H, dd, J=1.5, 4.5Hz) C001 (CDCl₃): 1.79-1.95(m, 3H), 2.14(m, 1H), 3.08(m, 1H), 3.26(dd, 374 J=12.6, 7.2Hz, 1H), 3.53(s, 3H), 3.65(m, 1H), 3.82-3.96(m, 2H), 6.65(s, 1H), 7.47(t, J=7.8Hz, 2H), 7.61(t, J=7.5Hz, 1H), 7.79(d, J=6.0Hz, 2H), 8.02(d, J=7.5Hz, 2H), 8.70(d, J=6.0Hz, 2H). C002 (CDCl₃): 1.81-1.92(m, 3H), 2.12(m, 1H), 3.08(m, 1H), 3.25(m, 392 1H), 3.52(s, 3H), 3.64(m, 1H), 3.75-3.92(m, 2H), 6.65(s, 1H), 7.12(t, J=8.4Hz, 2H), 7.84(m, 1H), 8.03(dd, J=7.8, 5.7Hz, 2H), 8.76(m, 1H). C005 (CDCl₃): 1.65-1.93(m, 3H), 2.13(m, 1H), 3.08(m, 1H), 3.25(dd, 405 J=12.9, 10.5Hz, 1H), 3.53(s, 3H), 3.65(m, 1H), 3.88(s, 3H), 3.77-3.94(m, 2H), 6.65(s, 1H), 6.93(dd, J=9.6, 1.2Hz, 2H), 7.80(d, J=6.0Hz, 2H), 8.00(dd, J=9.9, 1.2Hz, 2H), 8.70(d, J=6.0Hz, 2H). C006 (CDCl₃): 1.69-1.92(m, 3H), 2.12(m, 1H), 3.06(m, 1H), 3.21(dd, 405 J=12.9, 10.2Hz, 1H), 3.50(s, 3H), 3.60-3.83(m, 3H), 3.86(s, 3H), 6.66(s, 1H), 6.96-7.05(m, 2H), 7.45-7.57(m, 2H), 7.79(d, J=4.5Hz, 2H), 8.69(d, J=4.8Hz, 2H). C067 (CDCl₃): 1.83-2.14(m, 4H), 2.77(m, 1H), 3.06(m, 1H), 3.37(m, 390 1H), 3.45(s, 3H), 3.58(m, 1H), 3.90(m, 1H), 6.64(s, 1H), 7.13(m, 1H), 7.33(m, 2H), 7.53(d, J=8.2Hz, 2H), 7.64(m, 1H), 7.79(d, J=5.8Hz, 2H), 8.70(d, J=5.7Hz, 2H). C091 (CDCl₃): 1.81-2.01(6H, m), 2.70-2.75(2H, m), 3.00(1H, m), 430 3.25-3.92(6H, m), 3.35(3H, s), 6.61(1H, s), 7.12-7.26(4H, m), 7.72(2H, d, J=6.0Hz), 8.69(2H, d, J=6.0Hz). C092 (DMSO-d₆): 1.48-1.89(m, 10H), 2.92-3.07(m, 4H), 3.41(s, 3H), 382 3.42-3.72(m, 5H), 6.97(s, 1H), 8.38(d, J=5.1Hz, 2H), 8.92(d, J=5.1Hz, 2H). C094 (CDCl₃): 1.74-2.05(m, 4H), 3.08(m, 2H), 3.28(m, 1H), 3.51(s, 384 3H), 3.59-3.80(m, 10H), 6.63(s, 1H), 7.76(d, J=4.8Hz, 2H), 8.71(d, J=4.8Hz, 2H). C101 (CDCl₃): 3.37-3.50(m, 3H), 3.57(s, 3H), 3.90-4.00(m, 2H), 377 4.10-4.19(m, 1H), 5.14(dd, J=2.7, 9.3Hz, 1H), 6.70(s, 1H), 7.48(t, J=7.8Hz, 2H), 7.63(t, J=7.5Hz, 1H), 7.79(dd, J=1.5, 4.8Hz, 2H), 8.06(dd, J=1.2, 7.2Hz, 2H), 8.73(dd, J=1.8, 6.3Hz, 2H). C102 (CDCl₃): 3.30-3.50(m, 3H), 3.58(s, 3H), 3.85-4.17(m, 3H), 395 5.04(dd, J=2.7, 9.3Hz, 1H), 6.07(s, 1H), 7.14(dd, J=7.2, 8.7Hz, 2H), 7.78(dd, J=1.5, 4.8Hz, 2H), 8.11(m, 2H), 8.73(dd, J=1.5, 4.5Hz, 2H). C105 (CDCl₃): 1.65-1.93(3H, m), 2.13(1H, m), 3.08(1H, m), 3.25(1H, 405 dd, J=12.9, 10.5Hz), 3.53(3H, s), 3.65(1H, m), 3.88(3H, s), 3.77-3.94(2H, m), 6.65(1H, s), 6.93(2H, dd, J=9.6, 1.2Hz), 7.80(2H, d, J=6.0Hz), 8.00(2H, dd, J=9.9, 1.2Hz), 8.70(2H, d, J=6.0Hz). C106 (CDCl₃): 1.69-1.92(3H, m), 2.12(1H, m), 3.06(1H, m), 3.21(1H, 405 dd, J=12.9, 10.2Hz), 3.50(3H, s), 3.60-3.83(3H, m), 3.86(3H, s), 6.66(1H, s), 6.96-7.05(2H, m), 7.45-7.57(2H, m), 7.79(2H, d, J=4.5Hz), 8.69(2H, d, J=4.8Hz). C386 (CDCl₃): 1.80-2.11(4H, m), 3.07(1H, m), 3.26(1H, dd, J=13.1, 415 10.7Hz), 3.53(3H, s), 3.59-3.66(2H, m), 3.88(1H, m), 6.65(1H, s), 6.95(1H, d, J=4.2Hz), 7.62(1H, d, J=4.2Hz), 7.78(2H, dd, J=4.5, 1.6Hz), 8.71(2H, dd, J=4.5, 1.6Hz). C389 (CDCl₃): 3.3-3.7(3H, m), 3.57(3H, s), 3.9-4.0(2H, m), 4.1-4.2( 1H, m), 377 5.14(1H, dd, J=2.1, 9.0Hz), 6.70(1H, s), 7.4-7.5(2H, m), 7.6-7.7(1H, m), 7.78(2H, dd, J=1.2, 4.5Hz), 8.05(2H, dd, J=1.2, 7.2Hz), 8.73(2H, dd, J=0.9, 4.5Hz) C390 (CDCl₃): 3.3-3.7(3H, m), 3.57(3H, s), 3.9-4.0(2H, m), 4.1-4.2(1H, m), 377 5.14(1H, dd, J=2.1, 9.0Hz), 6.70(1H, s), 7.4-7.5(2H, m), 7.6-7.7(1H, m), 7.78(2H, dd, J=1.2, 4.5Hz), 8.05(2H, dd, J=1.2, 7.2Hz), 8.73(2H, dd, J=0.9, 4.5Hz) D001 (CDCl₃): 2.01-2.10(m, 4H), 3.16(m, 2H), 3.56(s+m, 3H+1H), 375 3.76(m, 2H), 6.69(s, 1H), 7.53(m, 2H), 7.63(m, 1H), 7.83(d, J=6.0Hz, 2H), 8.50(d, J=7.2Hz, 2H), 8.73(d, J=6.0Hz, 2H). D002 (CDCl₃): 1.93(m, 2H), 2.12(m, 2H), 3.12(m, 2H), 3.42(m, 1H), 393 3.53(s, 3H), 3.71(m, 2H), 6.68(s, 1H), 7.17(m, 1H), 7.28(m, 1H), 7.56(m, 1H), 7.80-7.86(m, 3H), 8.71(d, J=6.0Hz, 2H). D003 (CDCl₃): 1.94-2.10(m, 4H), 3.15(m, 2H), 3.49(m, 1H), 3.55(s, 393 3H), 3.75(m, 2H), 6.69(s, 1H), 7.31(m, 1H), 7.50(m, 1H), 7.65(m, 1H), 7.76(d, J=7.8Hz, 1H), 7.82(d, J=6.0Hz, 2H), 8.72(d, J=6.0Hz, 2H). D004 (CDCl₃): 1.95-2.06(m, 4H), 3.14(m, 2H), 3.50(m, 1H), 3.55(s, 393 3H), 3.75(m, 2H), 6.69(s, 1H), 7.19(t, J=8.6Hz, 2H), 7.82(d, J=6.0Hz, 2H), 8.02(m, 2H), 8.71(d, J=6.0Hz, 2H). D005 (CDCl₃): 1.89(m, 2H), 2.08(m, 2H), 3.06(m, 2H), 3.50(m, 1H), 405 3.53(s, 3H), 3.67(m, 2H), 3.93(s, 3H), 6.66(s, 1H), 6.98-7.06(m, 2H), 7.49(m, 1H), 7.61(m, 1H), 7.81(d, J=6.0Hz, 2H), 8.71(d, J=6.0Hz, 2H). D006 (CDCl₃): 1.94-2.10(m, 4H), 3.14(m, 2H), 3.50(m, 1H), 3.54(s, 405 3H), 3.74(m, 2H), 3.88(s, 3H), 6.68(s, 1H), 7.15(m, 1H), 7.39-7.57(m, 3H), 7.82(d, J=6.3Hz, 2H), 8.71(d, J=6.3Hz, 2H). D007 (CDCl₃): 1.99-2.06(m, 4H), 3.13(m, 2H), 3.50(m, 1H), 3.55(s, 405 3H), 3.75(m, 2H), 3.90(s, 3H), 6.68(s, 1H), 6.99(d, J=9.0Hz, 2H), 7.82(d, J=6.0Hz, 2H), 7.98(d, J=9.0Hz, 2H), 8.71(d, J=6.0Hz, 2H). D008 (CDCl₃): 1.94-2.06(m, 4H), 3.15(m, 2H), 3.49(m, 1H), 3.54(s, 409 3H), 3.75(m, 2H), 6.69(s, 1H), 7.44-7.60(m, 2H), 7.81-7.93(m, 3H), 7.94(s, 1H), 8.71(d, J=5.7Hz, 2H). D009 (CDCl₃): 1.94-2.06(m, 4H), 3.13(m, 2H), 3.49(m, 1H), 3.54(s, 409 3H), 3.74(m, 2H), 6.69(s, 1H), 7.49(d, J=8.4Hz, 2H), 7.81(d, J=6.0Hz, 2H), 7.92(d, J=8.4Hz, 2H), 8.71(d, J=6.0Hz, 2H). D0010 (CDCl₃): 1.95-2.06(m, 4H), 3.13(m, 2H), 3.48(m, 1H), 3.54(s, 454 3H), 3.74(m, 2H), 6.68(s, 1H), 7.66(d, J=8.4Hz, 2H), 7.80-7.86(m, 4H), 8.71(d, J=6.0Hz, 2H). D011 (CDCl₃): 1.89(m, 2H), 2.08(m, 2H), 3.06(m, 2H), 3.38(m, 1H), 435 3.52(s, 3H), 3.67(m, 2H), 3.91(s, 3H), 3.92(s, 3H), 6.66(s, 1H), 7.02-7.16(m, 3H), 7.80(d, J=6.0Hz, 2H), 8.71(d, J=6.0Hz, 2H). D012 (CDCl₃): 1.93(m, 2H), 2.10(m, 2H), 3.11(m, 2H), 3.38(m, 1H), 411 3.53(s, 3H), 3.72(m, 2H), 6.68(s, 1H), 6.88-7.04(m, 2H), 7.81(d, J=5Hz, 2H), 7.91(m, 1H), 8.71(d, J=5Hz, 2H). D013 (CDCl₃): 1.95-2.06(m, 4H), 3.14(m, 2H), 3.46(m, 1H), 3.54(s, 411 3H), 3.75(m, 2H), 6.69(s, 1H), 7.32(m, 1H), 7.75-7.86(m, 4H), 8.71(d, J=5.9Hz, 2H). D014 (CDCl₃): 2.06-2.08(m, 4H), 3.12(m, 2H), 3.38(m, 1H), 3.55(s, 381 3H), 3.76(m, 2H), 6.69(s, 1H), 7.19(m, 1H), 7.71(d, J=5.2Hz, 2H), 7.79-7.83(m, 3H), 8.71(d, J=5.6Hz, 2H). D015 (CDCl₃): 1.95-2.07(m, 4H), 3.11(m, 2H), 3.37(m, 1H), 3.55(s, 365 3H), 3.75(m, 2H), 6.60(m, 1H), 6.68(s, 1H), 7.29(m, 1H), 7.63(s, 1H), 7.82(d, J=6.0Hz, 2H), 8.71(d, J=6.0Hz, 2H). D016 (CDCl₃): 1.95(m, 2H), 2.12(m, 2H), 3.18(m, 2H), 3.55(s, 3H), 376 3.76(m, 2H), 4.16(m, 1H), 6.67(s, 1H), 7.52(m, 1H), 7.82-7.91(m, 3H), 8.08(d, J=8.3Hz, 1H), 8.70-8.72(m, 3H). D017 (CDCl₃): 2.17-2.28(m, 4H), 3.16(m, 2H), 3.31(m, 1H), 3.57(s, 414 3H), 3.80(m, 2H), 6.70(s, 1H), 6.72(d, J=3.7Hz, 1H), 7.28-7.42(m, 2H), 7.52(d, J=3.7Hz, 1H), 7.60(d, J=7.7Hz, 1H), 7.82(d, J=6.0Hz, 2H), 8.49(d, J=8.1Hz, 1H), 8.72(d, J=6.0Hz, 2H). D018 (CDCl₃): 1.83(m, 2H), 1.95-2.18(m, 4H), 2.73(t, J=6.5Hz, 2H), 430 2.86(m, 2H), 3.13(m, 1H), 3.52(s, 3H), 3.65(m, 2H), 3.82(t, J=6.8Hz, 2H), 6.65(s, 1H), 7.21-7.26(m, 4H), 7.78(d, J=6.0Hz, 2H), 8.69(d, J=6.0Hz, 2H). D019 (CDCl₃): 1.98-2.21(m, 4H), 2.76(m, 1H), 3.05(m, 2H), 3.25(t, 416 J=8.3Hz, 2H), 3.55(s, 3H), 3.77(m, 2H), 4.20(t, J=8.3Hz, 2H), 6.68(s, 1H), 7.05(m, 1H), 7.20-7.27(m, 2H), 7.82(d, J=5.9Hz, 2H), 8.26(d, J=8.2Hz, 1H), 8.71(d, J=5.9Hz, 2H). D020 (CDCl₃): 1.94-2.18(m, 4H), 2.81-3.08(m, 5H), 3.54(s, 3H), 430 3.71-3.89(m, 4H), 4.72-4.77(m, 2H), 6.67(s, 1H), 7.19-7.26(m, 4H), 7.81(d, J=6.0Hz, 2H), 8.71(d, J=6.0Hz, 2H). D021 (CDCl₃): 2.02-2.09(m, 4H), 3.10(m, 2H), 3.29(m, 1H), 3.54(s, 415 3H), 3.75(m, 2H), 6.69(s, 1H), 7.01(d, J=3.9Hz, 1H), 7.57(d, J=3.9Hz, 1H), 7.81(d, J=6.2Hz, 2H), 8.71(d, J=6.2Hz, 2H). D022 (CDCl₃): 1.98-2.10(m, 4H), 3.16(m, 2H), 3.55(s, 3H), 3.58(m, 451 1H), 3.76(m, 2H), 6.69(s, 1H), 7.40-7.52(m, 3H), 7.64(d, J=7.8Hz, 2H), 7.73(d, J=8.4Hz, 1H), 7.82(d, J=6.0Hz, 2H), 8.06(d, J=8.4Hz, 2H), 8.72(d, J=6.0Hz, 2H). D023 (CDCl₃): 1.57-1.77(m, 4H), 2.30(m, 1H), 2.59(m, 2H), 3.43(s, 451 3H), 3.49(m, 2H), 6.62(s, 1H), 7.35-7.53(m, 8H), 7.57(m, 1H), 7.74(d, J=5.9Hz, 2H), 8.69(d, J=5.9Hz, 2H). D024 (CDCl₃): 1.97-2.12(m, 4H), 3.11(m, 2H), 3.50(m, 1H), 3.54(s, 425 3H), 3.73(m, 2H), 6.68(s, 1H), 7.51-7.61(m, 3H), 7.80-7.82(m, 3H), 7.92(m, 1H), 8.02(d, J=8.4Hz, 1H), 8.34(d, J=7.5Hz, 1H), 8.71(d, J=6.0Hz, 2H). D025 (CDCl₃): 1.89(m, 2H), 2.06(m, 2H), 3.06(m, 2H), 3.51(m, 1H), 423 3.53(s, 3H), 3.68(m, 2H), 3.94(s, 3H), 6.70(s, 1H), 6.68-6.78(m, 2H), 7.70(dd, J=8.7, 6.9Hz, 1H), 7.81(d, J=6.0Hz, 2H), 8.71(d, J=6.0Hz, 2H). Test Example: Inhibitory activity of the medicament of the present invention against P-GS1 phosphorylation by bovine cerebral TPK1

A mixture containing 100 mM MES-sodium hydroxide (pH 6.5), 1 mM magnesium acetate, 0.5 mM EGTA, 5 mM β-mercaptoethanol, 0.02% Tween 20, 10% glycerol, 12 g g/ml P-GS1, 41.7 μM [γ-³²P] ATP (68 kBq/ml), bovine cerebral TPK1 and a compound shown in Table (a final mixture contained 1.7% DMSO deriving from a solution of a test compound prepared in the presence of 10% DMSO) was used as a reaction system. The phosphorylation was started by adding ATP, and the reaction was conducted at 25° C. for 2 hours, and then stopped by adding 21% perchloric acid on ice cooling. The reaction mixture was centrifuged at 12,000 rpm for 5 minutes and adsorbed on P81 paper (Whatmann), and then the paper was washed four times with 75 mM phosphoric acid, three times with water and once with acetone. The paper was dried, and the residual radioactivity was measured using a liquid scintillation counter. The results are shown in the table below. The test compound markedly inhibited the P-GS1 phosphorylation by TPK1. The results strongly suggest that the medicaments of the present invention inhibit the TPK1 activity, thereby suppress the A β neurotoxicity and the PHF formation, and that the medicaments of the present invention are effective for preventive and/or therapeutic treatment of Alzheimer disease and the above-mentioned diseases. TABLE 3 Compound No. IC₅₀(nM) A001 8.9 A002 27 A003 25 A006 13 B010 6 B037 4.8 B046 8.3 B051 1.9 B054 4 B063 6 B079 3.3 B084 1.1 B085 1.4 B087 5 B088 6 B090 1.1 B091 1.2 B093 0.28 B094 1.2 B097 2.8 B100 4.7 B102 0.62 B103 0.36 B104 10.6 B105 1.6 B106 1.4 B107 50 B108 6.7 B109 7.7 B110 8.2 B112 4.7 B113 4.8 B120 54 B122 63 B128 30 B130 52.9 B140 8 B143 56 B184 8 B185 0.67 B186 1.9 B187 2 B189 5 B220 1.1 B217 70.3 B225 64 B234 30 B235 26.9 B236 11 B238 7.8 B239 17 B240 1.2 B241 0.9 B242 12 B243 0.906 B244 0.3 B245 0.44 B246 27 B247 72 B248 32 B249 10 B251 40 B252 5.2 B253 15 B254 3.9 B255 21 B256 1.1 B257 67 B258 12 B259 4.5 B260 0.76 B261 1.3 B262 1.1 B263 1.2 B264 15 B268 13 B269 1.5 B270 0.79 B271 3.2 B272 0.98 B273 1.9 B274 3.4 B275 2.1 B276 2.5 B277 8.1 B279 1.1 B280 9.3 B281 5.5 B282 17 B283 3.1 B284 9.8 B285 8.9 B286 17 B287 0.57 B288 40 B289 33 B290 2 B291 2 B292 1.5 B293 1.8 B294 1.2 B295 2.7 B296 2.5 B297 23 B298 94 C001 2.1 C002 8.4 C005 45 C006 9 C067 72 C091 23 C092 63 C101 3.5 C102 20.4 C105 45 C106 9 C386 10 C389 34 C390 1.0 D001 9 D002 23 D004 15 D007 18 D009 6 D011 11 D012 19 D013 19 D014 20 D017 10 D018 4.3 D019 8.1 D021 11 D022 7.8 D023 13 D024 19 D025 16

Formulation Example

(1) Tablets

The ingredients below were mixed by an ordinary method and compressed by using a conventional apparatus. Compound of Example 1  30 mg Crystalline cellulose  60 mg Corn starch 100 mg Lactose 200 mg Magnesium stearate  4 mg (2) Soft Capsules

The ingredients below were mixed by an ordinary method and filled in soft capsules. Compound of Example 1  30 mg Olive oil 300 mg Lecithin  20 mg

Industrial Applicability

The compounds of the present invention have TPK1 inhibitory activity and are useful as an active ingredient of a medicament for preventive and/or therapeutic treatment of diseases caused by abnormal advance of TPK1 such as neurodegenerative diseases (e.g. Alzheimer disease) and the above-mentioned diseases. 

1. A pyrimidone derivative represented by formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof:

wherein R¹ represents a C₁-C₁₂ alkyl group which may be substituted; R represents any one of groups represented by the following formulas (II) to (V):

wherein R² and R³ independently represent a hydrogen atom or a C₁-C₈ alkyl group; R⁴ represents a benzene ring which may be substituted, a naphthalene ring which may be substituted, an indan ring which may be substituted, a tetrahydronaphthalene ring which may be substituted, or an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, and having 5 to 10 ring-constituting atoms in total; R⁵ represents a C₁-C₈ alkyl group which may be substituted, a C₃-C₈ cycloalkyl group which may be substituted, a benzene ring which may be substituted, a naphthalene ring which may be substituted, an indan ring which may be substituted, a tetrahydronaphthalene ring which may be substituted, or an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom, and nitrogen atom, and having 5 to 10 ring-constituting atoms in total; R⁶ represents a hydrogen atom, a C₁-C₈ alkyl group which may be substituted, a benzene ring which may be substituted; or R⁵ and R⁶ may bind to each other to form together with the carbon to which R⁵ and R⁶ are attached an optionally substituted spiro carbocyclic ring having 3 to 11 ring-constituting atoms in total; R⁷ and R⁸ independently represent a hydrogen atom or a C₁-C₈ alkyl group, or R⁷ and R⁸ may combine to each other to form a C₂-C₆ alkylene group; R⁹ and R¹⁰ represent a C₁-C₈ alkyl group which may be substituted, a C₃-C₈ cycloalkyl group which may be substituted, a benzene ring which may be substituted, a naphthalene ring which may be substituted, an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom, and nitrogen atom, and having 5 to 10 ring-constituting atoms in total, or R⁹ and R¹⁰ represent —N(R¹¹)(R¹²) wherein R¹¹ represents a hydrogen atom, a C₁-C₈ alkyl group; and R¹² represents a C₁-C₈ alkyl group, a benzene ring which may be substituted, a naphthalene ring which may be substituted, or an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom, and nitrogen atom, and having 5 to 10 ring-constituting atoms in total; and X represents CH₂, O or NR¹³ wherein R¹³ represents a hydrogen atom or a C₁-C₈ alkyl group.
 2. The pyrimidone derivative or the salt thereof, or the solvate thereof or the hydrate thereof according to claim 1, wherein R¹ is methyl group.
 3. The pyrimidone derivative or the salt thereof, or the solvate thereof or the hydrate thereof according to claim 1, wherein R is the group represented by formula (II).
 4. The pyrimidone derivative or the salt thereof, or the solvate thereof or the hydrate thereof according to claim 3, wherein each of R² and R³ is hydrogen atom.
 5. A pyrimidone derivative which is selected from the group consisting of: 3-methyl-2-(2-oxo-2-phenylethylamino)-6-pyridin-4-yl-3H-pyrimidin-4-one; 3-methyl-2-(2-oxo-2-(3-fluorophenyl)ethylamino)-6-pyridin-4-yl-3H-pyrimidin-4-one; 3-methyl-2-(2-oxo-2-(4-fluorophenyl)ethylamino)-6-pyridin-4-yl-3H-pyrimidin-4-one; 3-methyl-2-(2-oxo-2-(3-chlorophenyl)ethylamino)-6-pyridin-4-yl-3H-pyrimidin-4-one; 3-methyl-2-(2-oxo-2-(3-methylphenyl)ethylamino)-6-pyridin-4-yl-3H-pyrimidin-4-one; or a salt thereof, or a solvate thereof or a hydrate thereof.
 6. The pyrimidone derivative or the salt thereof, or the solvate thereof or the hydrate thereof according to claim 1 or 2, wherein R is the group represented by formula (III).
 7. The pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof according to claim 6, wherein R⁶ is hydrogen atom.
 8. The pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof according to claim 7, wherein each of R⁷ and R⁸ is hydrogen atom.
 9. The pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof according to claim 7, wherein each of R⁷ and R⁸ is methyl group.
 10. A pyrimidone derivative which is selected from the group consisting of: 2-[2-(4-Fluorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; (S)-2-[2-(4-Fluorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(2-Fluorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; (S)-2-[2-(2-Fluorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(4-Chlorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(3-Chlorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(2-Chlorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; (S)-2-[2-(2-Chlorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(4-Bromophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; (S)-2-[2-(4-Bromophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(3-Bromophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; (S)-2-[2-(3-Bromophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(2-Bromophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(4-Methylphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(3-Methylphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(2-Methylphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; (S)-2-[2-(2-Methylphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(4-Cyanophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(3-Cyanophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; (S)-2-[2-(3-Cyanophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(2-Cyanophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(4-Methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; (S)-2-[2-(4-Methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(3-Methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; (S)-2-[2-(3-Methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(2-Methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; (S)-2-[2-(2-Methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(2-Ethoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(2-Trifluoromethoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(5-Fluoro-2-methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(4-Fluoro-2-methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; (S)-2-[2-(4-Fluoro-2-methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(2,5-Dimethoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; (S)-2-[2-(2,5-Dimethoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(2-Chloro-4,5-difluorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; (S)-2-[2-(2-Chloro-4,5-difluorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(2-Bromo-4-fluorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(2,4-Difluorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; (S)-2-[2-(2,4-Difluorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(2,6-Dimethoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; (S)-2-[2-(2,6-Dimethoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(2,4-Dimethoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; (S)-2-[2-(2,4-Dimethoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(2,6-Dichlorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; (S)-2-[2-(2,6-Dichlorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(2,6-Difluorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; (S)-2-[2-(2,6-Difluorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(2-Chloro-6-fluorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; (S)-2-[2-(2-Chloro-6-fluorophenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyridin-4-one; 2-[2-(4-Fluoro-3-methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(5-Cyano-2-methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; (S)-2-[2-(5-Cyano-2-methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(4-Cyano-2-methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; (S)-2-[2-(4-Cyano-2-methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(2,4-Difluoro-6-methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; (S)-2-[2-(2,4-Difluoro-6-methoxyphenyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(4-(Pyrrolidin-1-yl-methyl)phenyl)morpholino-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; (S)-2-[2-(4-(Pyrrolidin-1-yl-methyl)phenyl)morpholino-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(1-Naphthyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(2-Naphthyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; (S)-2-[2-(2-Naphthyl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(2,3-Dihydrobenzofuran-7-yl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; (S)-2-[2-(2,3-Dihydrobenzofuran-7-yl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(Benzofuran-2-yl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; and (S)-2-[2-(Benzofuran-2-yl)morpholin-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one or a salt thereof, or a solvate thereof or a hydrate thereof.
 11. The pyrimidone derivative or the salt thereof, or the solvate thereof or the hydrate thereof according to claim 1, wherein R is the group represented by formula (IV).
 12. The pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof according to claim 11, wherein R⁹ is a benzene ring which may be substituted.
 13. The pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof according to claim 11, wherein X is CH₂.
 14. The pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof according to claim 11, wherein X is O.
 15. A pyrimidone derivative which is selected from the group consisting of: 2-[3-(4-Fluorobenzoyl)piperidin-1-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-(3-Benzoylpiperidin-1-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[3-(2-Methoxybenzoyl)piperidin-1-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[3-(4-Methoxybenzoyl)piperidin-1-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(4-Fluorobenzoyl)morpholine-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-(2-Benzoylmorpholine-4-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(2-Methoxybenzoyl)morpholine-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[2-(4-Methoxybenzoyl)morpholine-4-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; or a salt thereof, or a solvate thereof or a hydrate thereof.
 16. The pyrimidone derivative or the salt thereof, or the solvate thereof or the hydrate thereof according to claim 1, wherein R is the group represented by formula (V).
 17. The pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof according to claim 16, wherein R¹⁰ is a benzene ring which may be substituted.
 18. The pyrimidone derivative or the salts thereof, or the solvate thereof or the hydrate thereof according to claim 16, wherein R¹⁰ is a heterocyclic ring having 1 to 4 hetero atoms selected oxygen atom, sulfur atom and nitrogen atom, and having total ring-constituting atoms of 5 to 10 which may be substituted.
 19. A pyrimidone derivative which is selected from the group consisting of: 2-[4-(4-Chlorobenzoyl)piperidin-1-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; 2-[4-(3,4-Dihydro-2H-quinoline-1-carbonyl)-piperidin-1-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one; and 2-[4-(2,3-Dihydroindole-1-carbonyl)-piperidin-1-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one, or a salt thereof, or a solvate thereof or a hydrate thereof.
 20. A medicament comprising as an active ingredient a substance selected from the group consisting of the pyrimidone derivative represented by formula (I) and a salt thereof, and a solvate thereof and a hydrate thereof according to claim
 1. 21. A tau protein kinase 1 inhibitor selected from the group consisting of the pyrimidone derivative represented by formula (I) and a salt thereof, and a solvate thereof and a hydrate thereof according to claim
 1. 22. The medicament according to claim 20 which is used for preventive and/or therapeutic treatment of a disease caused by tau protein kinase 1 hyperactivity.
 23. The medicament according to claim 20 which is used for preventive and/or therapeutic treatment of a neurodegenerative disease.
 24. The medicament according to claim 23, wherein the disease is selected from the group consisting of Alzheimer disease, ischemic cerebrovascular accidents, Down syndrome, cerebral bleeding due to cerebral amyloid angiopathy, progressive supranuclear palsy, subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis, Guam parkinsonism-dementia complex, Lewy body disease, Pick's disease, corticobasal degeneration, frontotemporal dementia, vascular dementia, traumatic injuries, brain and spinal cord trauma, peripheral neuropathies, retinopathies and glaucoma.
 25. The medicament according to claim 20, wherein the disease is selected from the group consisting of non-insulin dependent diabetes, obesity, manic depressive illness, schizophrenia, alopecia, breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia, and a virus-induced tumor.
 26. A pyrimidone derivative represented by formula (VI) or a salt thereof, or a solvate thereof or a hydrate thereof:

wherein R¹ represents a C₁-C₁₂ alkyl group which may be substituted.
 27. A pyrimidone derivative represented by formula (VII) or a salt thereof, or a solvate thereof or a hydrate thereof:

wherein R¹ represents a C₁-C₁₂ alkyl group which may be substituted. 